Antigen binding molecules to tigit

ABSTRACT

Provided herein are antigen binding molecules that bind to TIGIT, including antibodies and antigen binding fragments thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/829,422, filed Dec. 1, 2017, which claims the benefit of U.S.Provisional Application No. 62/429,639, filed on Dec. 2, 2016. Theabove-referenced applications are hereby incorporated by reference intheir entirety.

ELECTRONIC SEQUENCE LISTING

The present application is being filed along with an Electronic SequenceListing. The Electronic Sequence Listing is submitted as an ASCII textfile, created on Jul. 2, 2020, 632 KB. The information in the ElectronicSequence Listing is incorporated herein by reference in its entirety.

BACKGROUND Field

The present invention relates to antigen binding molecules that bind toTIGIT and the use thereof.

Description of the Related Art

TIGIT (T cell immunoreceptor with Ig and ITIM domains) has beenpreviously identified as a putative modulator of immune function (see,e.g., US patent publication no. US20040121370, incorporated herein byreference).

TIGIT is an immunomodulatory receptor expressed primarily on activated Tcells and NK cells. TIGIT is also known as VSIG9; VSTM3; and WUCAM. Itsstructure shows one extracellular immunoglobulin domain, a type 1transmembrane region and two ITIM motifs. TIGIT forms part of aco-stimulatory network that consists of positive (CD226) and negative(TIGIT) immunomodulatory receptors on T cells, and ligands expressed onAPCs (CD 155 and CD112).

The TIGIT protein includes an immunoreceptor tyrosine-based inhibitionmotif (ITIM) in its cytoplasmic tail domain. As with PD-1 and CTLA-4,the ITIM domain in the cytoplasmic region of TIGIT is predicted torecruit tyrosine phosphatases, such as SHP-1 and SHP-2, and subsequentde-phosphorylation of tyrosine residues with in the immunoreceptortyrosine-base activation motifs (IT AM) on T cell receptor (TCR)subunits. Hence, ligation of TIGIT by receptor-ligands CD 155 and CD112expressed by tumor cells or TAMS may contribute to the suppression ofTCR-signaling and T cell activation, which is involved in mountingeffective anti-tumor immunity.

SUMMARY

Some embodiments provided herein relate to antigen binding moleculesthat bind to TIGIT and comprise one or more of the sequence and/orstructural aspects outlined in FIGS. 2A-2R and 3A-3L.

In some embodiments, an isolated antigen binding molecule that competesfor binding to human TIGIT with an antibody comprises any one or more ofa CDR within any of SEQ ID NO. 1-SEQ ID NO: 97, SEQ ID NO: 195-SEQ IDNO: 209, SEQ ID NO: 225-SEQ ID NO: 310, SEQ ID NO: 98-SEQ ID NO: 194,SEQ ID NO: 210-SEQ ID NO: 224, or SEQ ID NO: 311-SEQ ID NO: 396 any ofin FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P,2Q, 2R, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises: (a) a heavy chain CDR1 comprising the amino acidsequence of any one of the HCDR1s in SEQ ID NO: 397, SEQ ID NO: 403. SEQID NO: 409, SEQ ID NO: 415, SEQ ID NO: 421, SEQ ID NO: 427, SEQ ID NO:433, SEQ ID NO: 439, SEQ ID NO: 445, SEQ ID NO: 451, SEQ ID NO: 457, SEQID NO: 463, SEQ ID NO: 469, SEQ ID NO: 475, SEQ ID NO: 481, SEQ ID NO:487, SEQ ID NO: 493, SEQ ID NO: 499, SEQ ID NO: 505, SEQ ID NO: 511, SEQID NO: 517, SEQ ID NO: 523, SEQ ID NO: 529, SEQ ID NO: 535, SEQ ID NO:541, SEQ ID NO: 547, SEQ ID NO: 553, SEQ ID NO: 559, SEQ ID NO: 565, SEQID NO: 571, SEQ ID NO: 577, SEQ ID NO: 583, SEQ ID NO: 589, SEQ ID NO:595, SEQ ID NO: 601, SEQ ID NO: 607, SEQ ID NO: 613, SEQ ID NO: 619, SEQID NO: 625, SEQ ID NO: 631, SEQ ID NO: 637, SEQ ID NO: 643, SEQ ID NO:649, SEQ ID NO: 655, SEQ ID NO: 661, SEQ ID NO: 667, SEQ ID NO: 673, SEQID NO: 679, SEQ ID NO: 685, SEQ ID NO: 691, SEQ ID NO: 697, SEQ ID NO:703, SEQ ID NO: 709, SEQ ID NO: 715, SEQ ID NO: 721, SEQ ID NO: 727, SEQID NO: 733, SEQ ID NO: 739, SEQ ID NO: 745, SEQ ID NO: 751, SEQ ID NO:757, SEQ ID NO: 763, SEQ ID NO: 769, SEQ ID NO: 775, SEQ ID NO: 781, SEQID NO: 787, SEQ ID NO: 793, SEQ ID NO: 799, SEQ ID NO: 805, SEQ ID NO:811, SEQ ID NO: 817, SEQ ID NO: 823, SEQ ID NO: 829, SEQ ID NO: 835, SEQID NO: 841, SEQ ID NO: 847, SEQ ID NO: 853, SEQ ID NO: 859, SEQ ID NO:865, SEQ ID NO: 871, SEQ ID NO: 877, SEQ ID NO: 883, SEQ ID NO: 889, SEQID NO: 895, SEQ ID NO: 901, SEQ ID NO: 907, SEQ ID NO: 913, SEQ ID NO:919, SEQ ID NO: 925, SEQ ID NO: 931, SEQ ID NO: 937, SEQ ID NO: 943, SEQID NO: 949, SEQ ID NO: 955, SEQ ID NO: 961, SEQ ID NO: 967, SEQ ID NO:973, SEQ ID NO: 979, SEQ ID NO: 985, SEQ ID NO: 991, SEQ ID NO: 997, SEQID NO: 1003, SEQ ID NO: 1009, SEQ ID NO: 1015, SEQ ID NO: 1021, SEQ IDNO: 1027, SEQ ID NO: 1033, SEQ ID NO: 1039, SEQ ID NO: 1045, SEQ ID NO:1051, SEQ ID NO: 1057, SEQ ID NO: 1063, SEQ ID NO: 1069, SEQ ID NO:1075, SEQ ID NO: 1081, SEQ ID NO: 1087, SEQ ID NO: 1093, SEQ ID NO:1099, SEQ ID NO: 1105, SEQ ID NO: 1111, SEQ ID NO: 1117, SEQ ID NO:1123, SEQ ID NO: 1129, SEQ ID NO: 1135, SEQ ID NO: 1141, SEQ ID NO:1147, SEQ ID NO: 1153, SEQ ID NO: 1159, SEQ ID NO: 1165, SEQ ID NO:1171, SEQ ID NO: 1177, SEQ ID NO: 1183, SEQ ID NO: 1189, SEQ ID NO:1195, SEQ ID NO: 1201, SEQ ID NO: 1207, SEQ ID NO: 1213, SEQ ID NO:1219, SEQ ID NO: 1225, SEQ ID NO: 1231, SEQ ID NO: 1237, SEQ ID NO:1243, SEQ ID NO: 1249, SEQ ID NO: 1255, SEQ ID NO: 1261, SEQ ID NO:1267, SEQ ID NO: 1273, SEQ ID NO: 1279, SEQ ID NO: 1285, SEQ ID NO:1291, SEQ ID NO: 1297, SEQ ID NO: 1303, SEQ ID NO: 1309, SEQ ID NO:1315, SEQ ID NO: 1321, SEQ ID NO: 1327, SEQ ID NO: 1333, SEQ ID NO:1339, SEQ ID NO: 1345, SEQ ID NO: 1351, SEQ ID NO: 1357, SEQ ID NO:1363, SEQ ID NO: 1369, SEQ ID NO: 1375, SEQ ID NO: 1381, SEQ ID NO:1387, SEQ ID NO: 1393, SEQ ID NO: 1399, SEQ ID NO: 1405, SEQ ID NO:1411, SEQ ID NO: 1417, SEQ ID NO: 1423, SEQ ID NO: 1429, SEQ ID NO:1435, SEQ ID NO: 1441, SEQ ID NO: 1447, SEQ ID NO: 1453, SEQ ID NO:1459, SEQ ID NO: 1465, SEQ ID NO: 1471, SEQ ID NO: 1477, SEQ ID NO:1483, SEQ ID NO: 1489, SEQ ID NO: 1495, SEQ ID NO: 1501, SEQ ID NO:1507, SEQ ID NO: 1513, SEQ ID NO: 1519, SEQ ID NO: 1593, SEQ ID NO: 1525SEQ ID NO: 1531, SEQ ID NO: 1537, SEQ ID NO: 1543, SEQ ID NO: 1549, SEQID NO: 1555, SEQ ID NO: 1561, SEQ ID NO: 1567, SEQ ID NO: 1573, SEQ IDNO: 1579, or SEQ ID NO: 1585 in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I,3J, 3K, or 3L; (b) a heavy chain CDR2 comprising the amino acid sequenceof any one of the HCDR2s in SEQ ID NO: 398, SEQ ID NO: 404, SEQ ID NO:410, SEQ ID NO: 416, SEQ ID NO: 422, SEQ ID NO: 428, SEQ ID NO: 434, SEQID NO: 440, SEQ ID NO: 446, SEQ ID NO: 452, SEQ ID NO: 458, SEQ ID NO:464, SEQ ID NO: 470, SEQ ID NO: 476, SEQ ID NO: 482, SEQ ID NO: 488, SEQID NO: 494, SEQ ID NO: 500, SEQ ID NO: 506, SEQ ID NO: 512, SEQ ID NO:518, SEQ ID NO: 524, SEQ ID NO: 530, SEQ ID NO: 536, SEQ ID NO: 542, SEQID NO: 548, SEQ ID NO: 554, SEQ ID NO: 560, SEQ ID NO: 566, SEQ ID NO:572, SEQ ID NO: 578, SEQ ID NO: 584, SEQ ID NO: 590, SEQ ID NO: 596, SEQID NO: 602, SEQ ID NO: 608, SEQ ID NO: 614, SEQ ID NO: 620, SEQ ID NO:626, SEQ ID NO: 632, SEQ ID NO: 638, SEQ ID NO: 644, SEQ ID NO: 650, SEQID NO: 656, SEQ ID NO: 662, SEQ ID NO: 668, SEQ ID NO: 674, SEQ ID NO:680, SEQ ID NO: 686, SEQ ID NO: 692, SEQ ID NO: 698, SEQ ID NO: 704, SEQID NO: 710, SEQ ID NO: 716, SEQ ID NO: 722, SEQ ID NO: 728, SEQ ID NO:734, SEQ ID NO: 740, SEQ ID NO: 746, SEQ ID NO: 752, SEQ ID NO: 758, SEQID NO: 764, SEQ ID NO: 770, SEQ ID NO: 776, SEQ ID NO: 782, SEQ ID NO:788, SEQ ID NO: 794, SEQ ID NO: 800, SEQ ID NO: 806, SEQ ID NO: 812, SEQID NO: 818, SEQ ID NO: 824, SEQ ID NO: 830, SEQ ID NO: 836, SEQ ID NO:842, SEQ ID NO: 848, SEQ ID NO: 854, SEQ ID NO: 860, SEQ ID NO: 866, SEQID NO: 872, SEQ ID NO: 878, SEQ ID NO: 884, SEQ ID NO: 890, SEQ ID NO:896, SEQ ID NO: 902, SEQ ID NO: 908, SEQ ID NO: 914, SEQ ID NO: 920, SEQID NO: 926, SEQ ID NO: 932, SEQ ID NO: 938, SEQ ID NO: 944, SEQ ID NO:950, SEQ ID NO: 956, SEQ ID NO: 962, SEQ ID NO: 968, SEQ ID NO: 974, SEQID NO: 980, SEQ ID NO: 986, SEQ ID NO: 992, SEQ ID NO: 998, SEQ ID NO:1004, SEQ ID NO: 1010, SEQ ID NO: 1016, SEQ ID NO: 1022, SEQ ID NO:1028, SEQ ID NO: 1034, SEQ ID NO: 1040, SEQ ID NO: 1046, SEQ ID NO:1052, SEQ ID NO: 1058, SEQ ID NO: 1064, SEQ ID NO: 1070, SEQ ID NO:1076, SEQ ID NO: 1082, SEQ ID NO: 1088, SEQ ID NO: 1094, SEQ ID NO:1100, SEQ ID NO: 1106, SEQ ID NO: 1112, SEQ ID NO: 1118, SEQ ID NO:1124, SEQ ID NO: 1130, SEQ ID NO: 1136, SEQ ID NO: 1142, SEQ ID NO:1148, SEQ ID NO: 1154, SEQ ID NO: 1160, SEQ ID NO: 1166, SEQ ID NO:1172, SEQ ID NO: 1178, SEQ ID NO: 1184, SEQ ID NO: 1190, SEQ ID NO:1196, SEQ ID NO: 1202, SEQ ID NO: 1208, SEQ ID NO: 1214, SEQ ID NO:1220, SEQ ID NO: 1226, SEQ ID NO: 1232, SEQ ID NO: 1238, SEQ ID NO:1244, SEQ ID NO: 1250, SEQ ID NO: 1256, SEQ ID NO: 1262, SEQ ID NO:1268, SEQ ID NO: 1274, SEQ ID NO: 1280, SEQ ID NO: 1286, SEQ ID NO:1292, SEQ ID NO: 1298, SEQ ID NO: 1304, SEQ ID NO: 1310, SEQ ID NO:1316, SEQ ID NO: 1322, SEQ ID NO: 1328, SEQ ID NO: 1334, SEQ ID NO:1340, SEQ ID NO: 1346, SEQ ID NO: 1352, SEQ ID NO: 1358, SEQ ID NO:1364, SEQ ID NO: 1370, SEQ ID NO: 1376, SEQ ID NO: 1382, SEQ ID NO:1388, SEQ ID NO: 1394, SEQ ID NO: 1400, SEQ ID NO: 1406, SEQ ID NO:1412, SEQ ID NO: 1418, SEQ ID NO: 1424, SEQ ID NO: 1430, SEQ ID NO:1436, SEQ ID NO: 1442, SEQ ID NO: 1448, SEQ ID NO: 1454, SEQ ID NO:1460, SEQ ID NO: 1466, SEQ ID NO: 1472, SEQ ID NO: 1478, SEQ ID NO:1484, SEQ ID NO: 1490, SEQ ID NO: 1496, SEQ ID NO: 1502, SEQ ID NO:1508, SEQ ID NO: 1514, SEQ ID NO: 1520, SEQ ID NO: 1594, SEQ ID NO:1526, SEQ ID NO: 1532, SEQ ID NO: 1538, SEQ ID NO: 1544, SEQ ID NO:1550, SEQ ID NO: 1556, SEQ ID NO: 1562, SEQ ID NO: 1568, SEQ ID NO:1574, SEQ ID NO: 1580, or SEQ ID NO: 1586 in FIG. 3A, 3B, 3C, 3D, 3E,3F, 3G, 3H, 3I, 3J, 3K, or 3L; and (c) a heavy chain CDR3 comprising theamino acid sequence of any one of the HCDR3s in SEQ ID NO: 399, SEQ IDNO: 405, SEQ ID NO: 411, SEQ ID NO: 417, SEQ ID NO: 423, SEQ ID NO: 429,SEQ ID NO: 435, SEQ ID NO: 441, SEQ ID NO: 447, SEQ ID NO: 453, SEQ IDNO: 459, SEQ ID NO: 465, SEQ ID NO: 471, SEQ ID NO: 477, SEQ ID NO: 483,SEQ ID NO: 489, SEQ ID NO: 495, SEQ ID NO: 501, SEQ ID NO: 507, SEQ IDNO: 513, SEQ ID NO: 519, SEQ ID NO: 525, SEQ ID NO: 531, SEQ ID NO: 537,SEQ ID NO: 543, SEQ ID NO: 549, SEQ ID NO: 555, SEQ ID NO: 561, SEQ IDNO: 567, SEQ ID NO: 573, SEQ ID NO: 579, SEQ ID NO: 585, SEQ ID NO: 591,SEQ ID NO: 597, SEQ ID NO: 603, SEQ ID NO: 609, SEQ ID NO: 615, SEQ IDNO: 621, SEQ ID NO: 627, SEQ ID NO: 633, SEQ ID NO: 639, SEQ ID NO: 645,SEQ ID NO: 651, SEQ ID NO: 657, SEQ ID NO: 663, SEQ ID NO: 669, SEQ IDNO: 675, SEQ ID NO: 681, SEQ ID NO: 687, SEQ ID NO: 693, SEQ ID NO: 699,SEQ ID NO: 705, SEQ ID NO: 711, SEQ ID NO: 717, SEQ ID NO: 723, SEQ IDNO: 729, SEQ ID NO: 735, SEQ ID NO: 741, SEQ ID NO: 747, SEQ ID NO: 753,SEQ ID NO: 759, SEQ ID NO: 765, SEQ ID NO: 771, SEQ ID NO: 777, SEQ IDNO: 783, SEQ ID NO: 789, SEQ ID NO: 795, SEQ ID NO: 801, SEQ ID NO: 807,SEQ ID NO: 813, SEQ ID NO: 819, SEQ ID NO: 825, SEQ ID NO: 831, SEQ IDNO: 837, SEQ ID NO: 843, SEQ ID NO: 849, SEQ ID NO: 855, SEQ ID NO: 861,SEQ ID NO: 867, SEQ ID NO: 873, SEQ ID NO: 879, SEQ ID NO: 885, SEQ IDNO: 891, SEQ ID NO: 897, SEQ ID NO: 903, SEQ ID NO: 909, SEQ ID NO: 915,SEQ ID NO: 921, SEQ ID NO: 927, SEQ ID NO: 933, SEQ ID NO: 939, SEQ IDNO: 945, SEQ ID NO: 951, SEQ ID NO: 957, SEQ ID NO: 963, SEQ ID NO: 969,SEQ ID NO: 975, SEQ ID NO: 981, SEQ ID NO: 987, SEQ ID NO: 993, SEQ IDNO: 999, SEQ ID NO: 1005, SEQ ID NO: 1011, SEQ ID NO: 1017, SEQ ID NO:1023, SEQ ID NO: 1029, SEQ ID NO: 1035, SEQ ID NO: 1041, SEQ ID NO:1047, SEQ ID NO: 1053, SEQ ID NO: 1059, SEQ ID NO: 1065, SEQ ID NO:1071, SEQ ID NO: 1077, SEQ ID NO: 1083, SEQ ID NO: 1089, SEQ ID NO:1095, SEQ ID NO: 1101, SEQ ID NO: 1107, SEQ ID NO: 1113, SEQ ID NO:1119, SEQ ID NO: 1125, SEQ ID NO: 1131, SEQ ID NO: 1137, SEQ ID NO:1143, SEQ ID NO: 1149, SEQ ID NO: 1155, SEQ ID NO: 1161, SEQ ID NO:1167, SEQ ID NO: 1173, SEQ ID NO: 1179, SEQ ID NO: 1185, SEQ ID NO:1191, SEQ ID NO: 1197, SEQ ID NO: 1203, SEQ ID NO: 1209, SEQ ID NO:1215, SEQ ID NO: 1221, SEQ ID NO: 1227, SEQ ID NO: 1233, SEQ ID NO:1239, SEQ ID NO: 1245, SEQ ID NO: 1251, SEQ ID NO: 1257, SEQ ID NO:1263, SEQ ID NO: 1269, SEQ ID NO: 1275, SEQ ID NO: 1281, SEQ ID NO:1287, SEQ ID NO: 1293, SEQ ID NO: 1299, SEQ ID NO: 1305, SEQ ID NO:1311, SEQ ID NO: 1317, SEQ ID NO: 1323, SEQ ID NO: 1329, SEQ ID NO:1335, SEQ ID NO: 1341, SEQ ID NO: 1347, SEQ ID NO: 1353, SEQ ID NO:1359, SEQ ID NO: 1365, SEQ ID NO: 1371, SEQ ID NO: 1377, SEQ ID NO:1383, SEQ ID NO: 1389, SEQ ID NO: 1395, SEQ ID NO: 1401, SEQ ID NO:1407, SEQ ID NO: 1413, SEQ ID NO: 1419, SEQ ID NO: 1425, SEQ ID NO:1431, SEQ ID NO: 1437, SEQ ID NO: 1443, SEQ ID NO: 1449, SEQ ID NO:1455, SEQ ID NO: 1461, SEQ ID NO: 1467, SEQ ID NO: 1473, SEQ ID NO:1479, SEQ ID NO: 1485, SEQ ID NO: 1491, SEQ ID NO: 1497, SEQ ID NO:1503, SEQ ID NO: 1509, SEQ ID NO: 1515, SEQ ID NO: 1521, SEQ ID NO:1595, SEQ ID NO: 1527, SEQ ID NO: 1533, SEQ ID NO: 1539, SEQ ID NO:1545, SEQ ID NO: 1551, SEQ ID NO: 1557, SEQ ID NO: 1563, SEQ ID NO:1569, SEQ ID NO: 1575, SEQ ID NO: 1581, or SEQ ID NO: 1587 in FIG. 3A,3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, wherein the HCDR1, HCDR2,and HCDR3 are from a same clone.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises: (a) a heavy chain CDR1 comprising the amino acidsequence of any of one of the HCDR1s in SEQ ID NO: 397, SEQ ID NO: 403.SEQ ID NO: 409, SEQ ID NO: 415, SEQ ID NO: 421, SEQ ID NO: 427, SEQ IDNO: 433, SEQ ID NO: 439, SEQ ID NO: 445, SEQ ID NO: 451, SEQ ID NO: 457,SEQ ID NO: 463, SEQ ID NO: 469, SEQ ID NO: 475, SEQ ID NO: 481, SEQ IDNO: 487, SEQ ID NO: 493, SEQ ID NO: 499, SEQ ID NO: 505, SEQ ID NO: 511,SEQ ID NO: 517, SEQ ID NO: 523, SEQ ID NO: 529, SEQ ID NO: 535, SEQ IDNO: 541, SEQ ID NO: 547, SEQ ID NO: 553, SEQ ID NO: 559, SEQ ID NO: 565,SEQ ID NO: 571, SEQ ID NO: 577, SEQ ID NO: 583, SEQ ID NO: 589, SEQ IDNO: 595, SEQ ID NO: 601, SEQ ID NO: 607, SEQ ID NO: 613, SEQ ID NO: 619,SEQ ID NO: 625, SEQ ID NO: 631, SEQ ID NO: 637, SEQ ID NO: 643, SEQ IDNO: 649, SEQ ID NO: 655, SEQ ID NO: 661, SEQ ID NO: 667, SEQ ID NO: 673,SEQ ID NO: 679, SEQ ID NO: 685, SEQ ID NO: 691, SEQ ID NO: 697, SEQ IDNO: 703, SEQ ID NO: 709, SEQ ID NO: 715, SEQ ID NO: 721, SEQ ID NO: 727,SEQ ID NO: 733, SEQ ID NO: 739, SEQ ID NO: 745, SEQ ID NO: 751, SEQ IDNO: 757, SEQ ID NO: 763, SEQ ID NO: 769, SEQ ID NO: 775, SEQ ID NO: 781,SEQ ID NO: 787, SEQ ID NO: 793, SEQ ID NO: 799, SEQ ID NO: 805, SEQ IDNO: 811, SEQ ID NO: 817, SEQ ID NO: 823, SEQ ID NO: 829, SEQ ID NO: 835,SEQ ID NO: 841, SEQ ID NO: 847, SEQ ID NO: 853, SEQ ID NO: 859, SEQ IDNO: 865, SEQ ID NO: 871, SEQ ID NO: 877, SEQ ID NO: 883, SEQ ID NO: 889,SEQ ID NO: 895, SEQ ID NO: 901, SEQ ID NO: 907, SEQ ID NO: 913, SEQ IDNO: 919, SEQ ID NO: 925, SEQ ID NO: 931, SEQ ID NO: 937, SEQ ID NO: 943,SEQ ID NO: 949, SEQ ID NO: 955, SEQ ID NO: 961, SEQ ID NO: 967, SEQ IDNO: 973, SEQ ID NO: 979, SEQ ID NO: 985, SEQ ID NO: 991, SEQ ID NO: 997,SEQ ID NO: 1003, SEQ ID NO: 1009, SEQ ID NO: 1015, SEQ ID NO: 1021, SEQID NO: 1027, SEQ ID NO: 1033, SEQ ID NO: 1039, SEQ ID NO: 1045, SEQ IDNO: 1051, SEQ ID NO: 1057, SEQ ID NO: 1063, SEQ ID NO: 1069, SEQ ID NO:1075, SEQ ID NO: 1081, SEQ ID NO: 1087, SEQ ID NO: 1093, SEQ ID NO:1099, SEQ ID NO: 1105, SEQ ID NO: 1111, SEQ ID NO: 1117, SEQ ID NO:1123, SEQ ID NO: 1129, SEQ ID NO: 1135, SEQ ID NO: 1141, SEQ ID NO:1147, SEQ ID NO: 1153, SEQ ID NO: 1159, SEQ ID NO: 1165, SEQ ID NO:1171, SEQ ID NO: 1177, SEQ ID NO: 1183, SEQ ID NO: 1189, SEQ ID NO:1195, SEQ ID NO: 1201, SEQ ID NO: 1207, SEQ ID NO: 1213, SEQ ID NO:1219, SEQ ID NO: 1225, SEQ ID NO: 1231, SEQ ID NO: 1237, SEQ ID NO:1243, SEQ ID NO: 1249, SEQ ID NO: 1255, SEQ ID NO: 1261, SEQ ID NO:1267, SEQ ID NO: 1273, SEQ ID NO: 1279, SEQ ID NO: 1285, SEQ ID NO:1291, SEQ ID NO: 1297, SEQ ID NO: 1303, SEQ ID NO: 1309, SEQ ID NO:1315, SEQ ID NO: 1321, SEQ ID NO: 1327, SEQ ID NO: 1333, SEQ ID NO:1339, SEQ ID NO: 1345, SEQ ID NO: 1351, SEQ ID NO: 1357, SEQ ID NO:1363, SEQ ID NO: 1369, SEQ ID NO: 1375, SEQ ID NO: 1381, SEQ ID NO:1387, SEQ ID NO: 1393, SEQ ID NO: 1399, SEQ ID NO: 1405, SEQ ID NO:1411, SEQ ID NO: 1417, SEQ ID NO: 1423, SEQ ID NO: 1429, SEQ ID NO:1435, SEQ ID NO: 1441, SEQ ID NO: 1447, SEQ ID NO: 1453, SEQ ID NO:1459, SEQ ID NO: 1465, SEQ ID NO: 1471, SEQ ID NO: 1477, SEQ ID NO:1483, SEQ ID NO: 1489, SEQ ID NO: 1495, SEQ ID NO: 1501, SEQ ID NO:1507, SEQ ID NO: 1513, SEQ ID NO: 1519, SEQ ID NO: 1593, SEQ ID NO: 1525SEQ ID NO: 1531, SEQ ID NO: 1537, SEQ ID NO: 1543, SEQ ID NO: 1549, SEQID NO: 1555, SEQ ID NO: 1561, SEQ ID NO: 1567, SEQ ID NO: 1573, SEQ IDNO: 1579, or SEQ ID NO: 1585 in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I,3J, 3K, or 3L; (b) a heavy chain CDR2 comprising the amino acid sequenceof any one of the HCDR2s in SEQ ID NO: 398, SEQ ID NO: 404, SEQ ID NO:410, SEQ ID NO: 416, SEQ ID NO: 422, SEQ ID NO: 428, SEQ ID NO: 434, SEQID NO: 440, SEQ ID NO: 446, SEQ ID NO: 452, SEQ ID NO: 458, SEQ ID NO:464, SEQ ID NO: 470, SEQ ID NO: 476, SEQ ID NO: 482, SEQ ID NO: 488, SEQID NO: 494, SEQ ID NO: 500, SEQ ID NO: 506, SEQ ID NO: 512, SEQ ID NO:518, SEQ ID NO: 524, SEQ ID NO: 530, SEQ ID NO: 536, SEQ ID NO: 542, SEQID NO: 548, SEQ ID NO: 554, SEQ ID NO: 560, SEQ ID NO: 566, SEQ ID NO:572, SEQ ID NO: 578, SEQ ID NO: 584, SEQ ID NO: 590, SEQ ID NO: 596, SEQID NO: 602, SEQ ID NO: 608, SEQ ID NO: 614, SEQ ID NO: 620, SEQ ID NO:626, SEQ ID NO: 632, SEQ ID NO: 638, SEQ ID NO: 644, SEQ ID NO: 650, SEQID NO: 656, SEQ ID NO: 662, SEQ ID NO: 668, SEQ ID NO: 674, SEQ ID NO:680, SEQ ID NO: 686, SEQ ID NO: 692, SEQ ID NO: 698, SEQ ID NO: 704, SEQID NO: 710, SEQ ID NO: 716, SEQ ID NO: 722, SEQ ID NO: 728, SEQ ID NO:734, SEQ ID NO: 740, SEQ ID NO: 746, SEQ ID NO: 752, SEQ ID NO: 758, SEQID NO: 764, SEQ ID NO: 770, SEQ ID NO: 776, SEQ ID NO: 782, SEQ ID NO:788, SEQ ID NO: 794, SEQ ID NO: 800, SEQ ID NO: 806, SEQ ID NO: 812, SEQID NO: 818, SEQ ID NO: 824, SEQ ID NO: 830, SEQ ID NO: 836, SEQ ID NO:842, SEQ ID NO: 848, SEQ ID NO: 854, SEQ ID NO: 860, SEQ ID NO: 866, SEQID NO: 872, SEQ ID NO: 878, SEQ ID NO: 884, SEQ ID NO: 890, SEQ ID NO:896, SEQ ID NO: 902, SEQ ID NO: 908, SEQ ID NO: 914, SEQ ID NO: 920, SEQID NO: 926, SEQ ID NO: 932, SEQ ID NO: 938, SEQ ID NO: 944, SEQ ID NO:950, SEQ ID NO: 956, SEQ ID NO: 962, SEQ ID NO: 968, SEQ ID NO: 974, SEQID NO: 980, SEQ ID NO: 986, SEQ ID NO: 992, SEQ ID NO: 998, SEQ ID NO:1004, SEQ ID NO: 1010, SEQ ID NO: 1016, SEQ ID NO: 1022, SEQ ID NO:1028, SEQ ID NO: 1034, SEQ ID NO: 1040, SEQ ID NO: 1046, SEQ ID NO:1052, SEQ ID NO: 1058, SEQ ID NO: 1064, SEQ ID NO: 1070, SEQ ID NO:1076, SEQ ID NO: 1082, SEQ ID NO: 1088, SEQ ID NO: 1094, SEQ ID NO:1100, SEQ ID NO: 1106, SEQ ID NO: 1112, SEQ ID NO: 1118, SEQ ID NO:1124, SEQ ID NO: 1130, SEQ ID NO: 1136, SEQ ID NO: 1142, SEQ ID NO:1148, SEQ ID NO: 1154, SEQ ID NO: 1160, SEQ ID NO: 1166, SEQ ID NO:1172, SEQ ID NO: 1178, SEQ ID NO: 1184, SEQ ID NO: 1190, SEQ ID NO:1196, SEQ ID NO: 1202, SEQ ID NO: 1208, SEQ ID NO: 1214, SEQ ID NO:1220, SEQ ID NO: 1226, SEQ ID NO: 1232, SEQ ID NO: 1238, SEQ ID NO:1244, SEQ ID NO: 1250, SEQ ID NO: 1256, SEQ ID NO: 1262, SEQ ID NO:1268, SEQ ID NO: 1274, SEQ ID NO: 1280, SEQ ID NO: 1286, SEQ ID NO:1292, SEQ ID NO: 1298, SEQ ID NO: 1304, SEQ ID NO: 1310, SEQ ID NO:1316, SEQ ID NO: 1322, SEQ ID NO: 1328, SEQ ID NO: 1334, SEQ ID NO:1340, SEQ ID NO: 1346, SEQ ID NO: 1352, SEQ ID NO: 1358, SEQ ID NO:1364, SEQ ID NO: 1370, SEQ ID NO: 1376, SEQ ID NO: 1382, SEQ ID NO:1388, SEQ ID NO: 1394, SEQ ID NO: 1400, SEQ ID NO: 1406, SEQ ID NO:1412, SEQ ID NO: 1418, SEQ ID NO: 1424, SEQ ID NO: 1430, SEQ ID NO:1436, SEQ ID NO: 1442, SEQ ID NO: 1448, SEQ ID NO: 1454, SEQ ID NO:1460, SEQ ID NO: 1466, SEQ ID NO: 1472, SEQ ID NO: 1478, SEQ ID NO:1484, SEQ ID NO: 1490, SEQ ID NO: 1496, SEQ ID NO: 1502, SEQ ID NO:1508, SEQ ID NO: 1514, SEQ ID NO: 1520, SEQ ID NO: 1594, SEQ ID NO:1526, SEQ ID NO: 1532, SEQ ID NO: 1538, SEQ ID NO: 1544, SEQ ID NO:1550, SEQ ID NO: 1556, SEQ ID NO: 1562, SEQ ID NO: 1568, SEQ ID NO:1574, SEQ ID NO: 1580, or SEQ ID NO: 1586 in FIG. 3A, 3B, 3C, 3D, 3E,3F, 3G, 3H, 3I, 3J, 3K, or 3L; (c) a heavy chain CDR3 comprising theamino acid sequence of any one of the HCDR3s in SEQ ID NO: 399, SEQ IDNO: 405, SEQ ID NO: 411, SEQ ID NO: 417, SEQ ID NO: 423, SEQ ID NO: 429,SEQ ID NO: 435, SEQ ID NO: 441, SEQ ID NO: 447, SEQ ID NO: 453, SEQ IDNO: 459, SEQ ID NO: 465, SEQ ID NO: 471, SEQ ID NO: 477, SEQ ID NO: 483,SEQ ID NO: 489, SEQ ID NO: 495, SEQ ID NO: 501, SEQ ID NO: 507, SEQ IDNO: 513, SEQ ID NO: 519, SEQ ID NO: 525, SEQ ID NO: 531, SEQ ID NO: 537,SEQ ID NO: 543, SEQ ID NO: 549, SEQ ID NO: 555, SEQ ID NO: 561, SEQ IDNO: 567, SEQ ID NO: 573, SEQ ID NO: 579, SEQ ID NO: 585, SEQ ID NO: 591,SEQ ID NO: 597, SEQ ID NO: 603, SEQ ID NO: 609, SEQ ID NO: 615, SEQ IDNO: 621, SEQ ID NO: 627, SEQ ID NO: 633, SEQ ID NO: 639, SEQ ID NO: 645,SEQ ID NO: 651, SEQ ID NO: 657, SEQ ID NO: 663, SEQ ID NO: 669, SEQ IDNO: 675, SEQ ID NO: 681, SEQ ID NO: 687, SEQ ID NO: 693, SEQ ID NO: 699,SEQ ID NO: 705, SEQ ID NO: 711, SEQ ID NO: 717, SEQ ID NO: 723, SEQ IDNO: 729, SEQ ID NO: 735, SEQ ID NO: 741, SEQ ID NO: 747, SEQ ID NO: 753,SEQ ID NO: 759, SEQ ID NO: 765, SEQ ID NO: 771, SEQ ID NO: 777, SEQ IDNO: 783, SEQ ID NO: 789, SEQ ID NO: 795, SEQ ID NO: 801, SEQ ID NO: 807,SEQ ID NO: 813, SEQ ID NO: 819, SEQ ID NO: 825, SEQ ID NO: 831, SEQ IDNO: 837, SEQ ID NO: 843, SEQ ID NO: 849, SEQ ID NO: 855, SEQ ID NO: 861,SEQ ID NO: 867, SEQ ID NO: 873, SEQ ID NO: 879, SEQ ID NO: 885, SEQ IDNO: 891, SEQ ID NO: 897, SEQ ID NO: 903, SEQ ID NO: 909, SEQ ID NO: 915,SEQ ID NO: 921, SEQ ID NO: 927, SEQ ID NO: 933, SEQ ID NO: 939, SEQ IDNO: 945, SEQ ID NO: 951, SEQ ID NO: 957, SEQ ID NO: 963, SEQ ID NO: 969,SEQ ID NO: 975, SEQ ID NO: 981, SEQ ID NO: 987, SEQ ID NO: 993, SEQ IDNO: 999, SEQ ID NO: 1005, SEQ ID NO: 1011, SEQ ID NO: 1017, SEQ ID NO:1023, SEQ ID NO: 1029, SEQ ID NO: 1035, SEQ ID NO: 1041, SEQ ID NO:1047, SEQ ID NO: 1053, SEQ ID NO: 1059, SEQ ID NO: 1065, SEQ ID NO:1071, SEQ ID NO: 1077, SEQ ID NO: 1083, SEQ ID NO: 1089, SEQ ID NO:1095, SEQ ID NO: 1101, SEQ ID NO: 1107, SEQ ID NO: 1113, SEQ ID NO:1119, SEQ ID NO: 1125, SEQ ID NO: 1131, SEQ ID NO: 1137, SEQ ID NO:1143, SEQ ID NO: 1149, SEQ ID NO: 1155, SEQ ID NO: 1161, SEQ ID NO:1167, SEQ ID NO: 1173, SEQ ID NO: 1179, SEQ ID NO: 1185, SEQ ID NO:1191, SEQ ID NO: 1197, SEQ ID NO: 1203, SEQ ID NO: 1209, SEQ ID NO:1215, SEQ ID NO: 1221, SEQ ID NO: 1227, SEQ ID NO: 1233, SEQ ID NO:1239, SEQ ID NO: 1245, SEQ ID NO: 1251, SEQ ID NO: 1257, SEQ ID NO:1263, SEQ ID NO: 1269, SEQ ID NO: 1275, SEQ ID NO: 1281, SEQ ID NO:1287, SEQ ID NO: 1293, SEQ ID NO: 1299, SEQ ID NO: 1305, SEQ ID NO:1311, SEQ ID NO: 1317, SEQ ID NO: 1323, SEQ ID NO: 1329, SEQ ID NO:1335, SEQ ID NO: 1341, SEQ ID NO: 1347, SEQ ID NO: 1353, SEQ ID NO:1359, SEQ ID NO: 1365, SEQ ID NO: 1371, SEQ ID NO: 1377, SEQ ID NO:1383, SEQ ID NO: 1389, SEQ ID NO: 1395, SEQ ID NO: 1401, SEQ ID NO:1407, SEQ ID NO: 1413, SEQ ID NO: 1419, SEQ ID NO: 1425, SEQ ID NO:1431, SEQ ID NO: 1437, SEQ ID NO: 1443, SEQ ID NO: 1449, SEQ ID NO:1455, SEQ ID NO: 1461, SEQ ID NO: 1467, SEQ ID NO: 1473, SEQ ID NO:1479, SEQ ID NO: 1485, SEQ ID NO: 1491, SEQ ID NO: 1497, SEQ ID NO:1503, SEQ ID NO: 1509, SEQ ID NO: 1515, SEQ ID NO: 1521, SEQ ID NO:1595, SEQ ID NO: 1527, SEQ ID NO: 1533, SEQ ID NO: 1539, SEQ ID NO:1545, SEQ ID NO: 1551, SEQ ID NO: 1557, SEQ ID NO: 1563, SEQ ID NO:1569, SEQ ID NO: 1575, SEQ ID NO: 1581, or SEQ ID NO: 1587 in FIG. 3A,3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L; (d) a light chain CDR1comprising the amino acid sequence of any one of the LCDR1s in SEQ IDNO: 400, SEQ ID NO: 406, SEQ ID NO: 412, SEQ ID NO: 418, SEQ ID NO: 424,SEQ ID NO: 430, SEQ ID NO: 436, SEQ ID NO: 442, SEQ ID NO: 448, SEQ IDNO: 454, SEQ ID NO: 460, SEQ ID NO: 466, SEQ ID NO: 472, SEQ ID NO: 478,SEQ ID NO: 484, SEQ ID NO: 490, SEQ ID NO: 496, SEQ ID NO: 502, SEQ IDNO: 508, SEQ ID NO: 514, SEQ ID NO: 520, SEQ ID NO: 526, SEQ ID NO: 532,SEQ ID NO: 538, SEQ ID NO: 544, SEQ ID NO: 550, SEQ ID NO: 556, SEQ IDNO: 562, SEQ ID NO: 568, SEQ ID NO: 574, SEQ ID NO: 580, SEQ ID NO: 586,SEQ ID NO: 592, SEQ ID NO: 598, SEQ ID NO: 604, SEQ ID NO: 610, SEQ IDNO: 616, SEQ ID NO: 622, SEQ ID NO: 628, SEQ ID NO: 634, SEQ ID NO: 640,SEQ ID NO: 646, SEQ ID NO: 652, SEQ ID NO: 658, SEQ ID NO: 664, SEQ IDNO: 670, SEQ ID NO: 676, SEQ ID NO: 682, SEQ ID NO: 688, SEQ ID NO: 694,SEQ ID NO: 700, SEQ ID NO: 706, SEQ ID NO: 712, SEQ ID NO: 718, SEQ IDNO: 724, SEQ ID NO: 730, SEQ ID NO: 736, SEQ ID NO: 742, SEQ ID NO: 748,SEQ ID NO: 754, SEQ ID NO: 760, SEQ ID NO: 766, SEQ ID NO: 772, SEQ IDNO: 778, SEQ ID NO: 784, SEQ ID NO: 790, SEQ ID NO: 796, SEQ ID NO: 802,SEQ ID NO: 808, SEQ ID NO: 814, SEQ ID NO: 820, SEQ ID NO: 826, SEQ IDNO: 832, SEQ ID NO: 838, SEQ ID NO: 844, SEQ ID NO: 850, SEQ ID NO: 856,SEQ ID NO: 862, SEQ ID NO: 868, SEQ ID NO: 874, SEQ ID NO: 880, SEQ IDNO: 886, SEQ ID NO: 892, SEQ ID NO: 898, SEQ ID NO: 904, SEQ ID NO: 910,SEQ ID NO: 916, SEQ ID NO: 922, SEQ ID NO: 928, SEQ ID NO: 934, SEQ IDNO: 940, SEQ ID NO: 946, SEQ ID NO: 952, SEQ ID NO: 958, SEQ ID NO: 964,SEQ ID NO: 970, SEQ ID NO: 976, SEQ ID NO: 982, SEQ ID NO: 988, SEQ IDNO: 994, SEQ ID NO: 1000, SEQ ID NO: 1006, SEQ ID NO: 1012, SEQ ID NO:1018, SEQ ID NO: 1024, SEQ ID NO: 1030, SEQ ID NO: 1036, SEQ ID NO:1042, SEQ ID NO: 1048, SEQ ID NO: 1054, SEQ ID NO: 1060, SEQ ID NO:1066, SEQ ID NO: 1072, SEQ ID NO: 1078, SEQ ID NO: 1084, SEQ ID NO:1090, SEQ ID NO: 1096, SEQ ID NO: 1102, SEQ ID NO: 1108, SEQ ID NO:1114, SEQ ID NO: 1120, SEQ ID NO: 1126, SEQ ID NO: 1132, SEQ ID NO:1138, SEQ ID NO: 1144, SEQ ID NO: 1150, SEQ ID NO: 1156, SEQ ID NO:1162, SEQ ID NO: 1168, SEQ ID NO: 1174, SEQ ID NO: 1180, SEQ ID NO:1186, SEQ ID NO: 1192, SEQ ID NO: 1198, SEQ ID NO: 1204, SEQ ID NO:1210, SEQ ID NO: 1216, SEQ ID NO: 1222, SEQ ID NO: 1228, SEQ ID NO:1234, SEQ ID NO: 1240, SEQ ID NO: 1246, SEQ ID NO: 1252, SEQ ID NO:1258, SEQ ID NO: 1264, SEQ ID NO: 1270, SEQ ID NO: 1276, SEQ ID NO:1282, SEQ ID NO: 1288, SEQ ID NO: 1294, SEQ ID NO: 1300, SEQ ID NO:1306, SEQ ID NO: 1312, SEQ ID NO: 1318, SEQ ID NO: 1324, SEQ ID NO:1330, SEQ ID NO: 1336, SEQ ID NO: 1342, SEQ ID NO: 1348, SEQ ID NO:1354, SEQ ID NO: 1360, SEQ ID NO: 1366, SEQ ID NO: 1372, SEQ ID NO:1378, SEQ ID NO: 1384, SEQ ID NO: 1390, SEQ ID NO: 1396, SEQ ID NO:1402, SEQ ID NO: 1408, SEQ ID NO: 1414, SEQ ID NO: 1420, SEQ ID NO:1426, SEQ ID NO: 1432, SEQ ID NO: 1438, SEQ ID NO: 1444, SEQ ID NO:1450. SEQ ID NO: 1456, SEQ ID NO: 1462, SEQ ID NO: 1468, SEQ ID NO:1474, SEQ ID NO: 1480, SEQ ID NO: 1486, SEQ ID NO: 1492, SEQ ID NO:1498, SEQ ID NO: 1504, SEQ ID NO: 1510, SEQ ID NO: 1516, SEQ ID NO:1522, SEQ ID NO: 1596, SEQ ID NO: 1528, SEQ ID NO: 1534, SEQ ID NO:1540, SEQ ID NO: 1546, SEQ ID NO: 1552, SEQ ID NO: 1558, SEQ ID NO:1564, SEQ ID NO: 1570, SEQ ID NO: 1576, SEQ ID NO: 1582, or SEQ ID NO:1588 in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L; (e) alight chain CDR2 comprising the amino acid sequence of any one of theLCDR2s in SEQ ID NO: 401, SEQ ID NO: 407, SEQ ID NO: 413, SEQ ID NO:419, SEQ ID NO: 425, SEQ ID NO: 431, SEQ ID NO: 437, SEQ ID NO: 443, SEQID NO: 449, SEQ ID NO: 455, SEQ ID NO: 461, SEQ ID NO: 467, SEQ ID NO:473, SEQ ID NO: 479, SEQ ID NO: 485, SEQ ID NO: 491, SEQ ID NO: 497, SEQID NO: 503, SEQ ID NO: 509, SEQ ID NO: 515, SEQ ID NO: 521, SEQ ID NO:527, SEQ ID NO: 533, SEQ ID NO: 539, SEQ ID NO: 545, SEQ ID NO: 551, SEQID NO: 557, SEQ ID NO: 563, SEQ ID NO: 569, SEQ ID NO: 575, SEQ ID NO:581, SEQ ID NO: 587, SEQ ID NO: 593, SEQ ID NO: 599, SEQ ID NO: 605, SEQID NO: 611, SEQ ID NO: 617, SEQ ID NO: 623, SEQ ID NO: 629, SEQ ID NO:635, SEQ ID NO: 641, SEQ ID NO: 647, SEQ ID NO: 653, SEQ ID NO: 659, SEQID NO: 665, SEQ ID NO: 671, SEQ ID NO: 677, SEQ ID NO: 683, SEQ ID NO:689, SEQ ID NO: 695, SEQ ID NO: 701, SEQ ID NO: 707, SEQ ID NO: 713, SEQID NO: 719, SEQ ID NO: 725, SEQ ID NO: 731, SEQ ID NO: 737, SEQ ID NO:743, SEQ ID NO: 749, SEQ ID NO: 755, SEQ ID NO: 761, SEQ ID NO: 767, SEQID NO: 773, SEQ ID NO: 779, SEQ ID NO: 785, SEQ ID NO: 791, SEQ ID NO:797, SEQ ID NO: 803, SEQ ID NO: 809, SEQ ID NO: 815, SEQ ID NO: 821, SEQID NO: 827, SEQ ID NO: 833, SEQ ID NO: 839, SEQ ID NO: 845, SEQ ID NO:851, SEQ ID NO: 857, SEQ ID NO: 863, SEQ ID NO: 869, SEQ ID NO: 875, SEQID NO: 881, SEQ ID NO: 887, SEQ ID NO: 893, SEQ ID NO: 899, SEQ ID NO:905, SEQ ID NO: 911, SEQ ID NO: 917, SEQ ID NO: 923, SEQ ID NO: 929, SEQID NO: 935, SEQ ID NO: 941, SEQ ID NO: 947, SEQ ID NO: 953, SEQ ID NO:959, SEQ ID NO: 965, SEQ ID NO: 971, SEQ ID NO: 977, SEQ ID NO: 983, SEQID NO: 989, SEQ ID NO: 995, SEQ ID NO: 1001, SEQ ID NO: 1007, SEQ ID NO:1013, SEQ ID NO: 1019, SEQ ID NO: 1025, SEQ ID NO: 1031, SEQ ID NO:1037, SEQ ID NO: 1043, SEQ ID NO: 1049, SEQ ID NO: 1055, SEQ ID NO:1061, SEQ ID NO: 1067, SEQ ID NO: 1073, SEQ ID NO: 1079, SEQ ID NO:1085, SEQ ID NO: 1091, SEQ ID NO: 1097, SEQ ID NO: 1103, SEQ ID NO:1109, SEQ ID NO: 1015, SEQ ID NO: 1121, SEQ ID NO: 1127, SEQ ID NO:1133, SEQ ID NO: 1139, SEQ ID NO: 1145, SEQ ID NO: 1151, SEQ ID NO:1157, SEQ ID NO: 1163, SEQ ID NO: 1169, SEQ ID NO: 1175, SEQ ID NO:1181, SEQ ID NO: 1187, SEQ ID NO: 1193, SEQ ID NO: 1199, SEQ ID NO:1205, SEQ ID NO: 1211, SEQ ID NO: 1217, SEQ ID NO: 1223, SEQ ID NO:1229, SEQ ID NO: 1235, SEQ ID NO: 1241, SEQ ID NO: 1247, SEQ ID NO:1253, SEQ ID NO: 1259, SEQ ID NO: 1265, SEQ ID NO: 1271, SEQ ID NO:1277, SEQ ID NO: 1283, SEQ ID NO: 1289, SEQ ID NO: 1295, SEQ ID NO:1301, SEQ ID NO: 1307, SEQ ID NO: 1313, SEQ ID NO: 1319, SEQ ID NO:1325, SEQ ID NO: 1331, SEQ ID NO: 1337, SEQ ID NO: 1343, SEQ ID NO:1349, SEQ ID NO: 1355, SEQ ID NO: 1361, SEQ ID NO: 1367, SEQ ID NO:1373, SEQ ID NO: 1379, SEQ ID NO: 1385, SEQ ID NO: 1391, SEQ ID NO:1397, SEQ ID NO: 1403, SEQ ID NO: 1409, SEQ ID NO: 1415, SEQ ID NO:1421, SEQ ID NO: 1427, SEQ ID NO: 1433, SEQ ID NO: 1439, SEQ ID NO:1445, SEQ ID NO: 1451, SEQ ID NO: 1457, SEQ ID NO: 1463, SEQ ID NO:1469, SEQ ID NO: 1475, SEQ ID NO: 1481, SEQ ID NO: 1487, SEQ ID NO:1493, SEQ ID NO: 1499, SEQ ID NO: 1505, SEQ ID NO: 1511, SEQ ID NO:1517, SEQ ID NO: 1523, SEQ ID NO: 1597, SEQ ID NO: 1529, SEQ ID NO:1535, SEQ ID NO: 1541, SEQ ID NO: 1547, SEQ ID NO: 1553, SEQ ID NO:1559, SEQ ID NO: 1565, SEQ ID NO: 1571, SEQ ID NO: 1577, SEQ ID NO:1583, or SEQ ID NO: 1589 in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J,3K, or 3L; and (f) a light chain CDR3 comprising the amino acid sequenceof any one of the LCDR3s in SEQ ID NO: 402, SEQ ID NO: 408, SEQ ID NO:414, SEQ ID NO: 420, SEQ ID NO: 426, SEQ ID NO: 432, SEQ ID NO: 438, SEQID NO: 444, SEQ ID NO: 450, SEQ ID NO: 456, SEQ ID NO: 462, SEQ ID NO:468, SEQ ID NO: 474, SEQ ID NO: 480, SEQ ID NO: 486, SEQ ID NO: 492, SEQID NO: 498, SEQ ID NO: 504, SEQ ID NO: 510, SEQ ID NO: 516, SEQ ID NO:522, SEQ ID NO: 528, SEQ ID NO: 534, SEQ ID NO: 540, SEQ ID NO: 546, SEQID NO: 552, SEQ ID NO: 558, SEQ ID NO: 564, SEQ ID NO: 570, SEQ ID NO:576, SEQ ID NO: 582, SEQ ID NO: 588, SEQ ID NO: 594, SEQ ID NO: 600, SEQID NO: 606, SEQ ID NO: 612, SEQ ID NO: 618, SEQ ID NO: 624, SEQ ID NO:630, SEQ ID NO: 636, SEQ ID NO: 642, SEQ ID NO: 648, SEQ ID NO: 654, SEQID NO: 660, SEQ ID NO: 666, SEQ ID NO: 672, SEQ ID NO: 678, SEQ ID NO:684, SEQ ID NO: 690, SEQ ID NO: 696, SEQ ID NO: 702, SEQ ID NO: 708, SEQID NO: 714, SEQ ID NO: 720, SEQ ID NO: 726, SEQ ID NO: 732, SEQ ID NO:738, SEQ ID NO: 744, SEQ ID NO: 750, SEQ ID NO: 756, SEQ ID NO: 762, SEQID NO: 768, SEQ ID NO: 774, SEQ ID NO: 780, SEQ ID NO: 786, SEQ ID NO:792, SEQ ID NO: 798, SEQ ID NO: 804, SEQ ID NO: 810, SEQ ID NO: 816, SEQID NO: 822, SEQ ID NO: 828, SEQ ID NO: 834, SEQ ID NO: 840, SEQ ID NO:846, SEQ ID NO: 852, SEQ ID NO: 858, SEQ ID NO: 864, SEQ ID NO: 870, SEQID NO: 876, SEQ ID NO: 882, SEQ ID NO: 888, SEQ ID NO: 894, SEQ ID NO:900, SEQ ID NO: 906, SEQ ID NO: 912, SEQ ID NO: 918, SEQ ID NO: 924, SEQID NO: 930, SEQ ID NO: 936, SEQ ID NO: 942, SEQ ID NO: 948, SEQ ID NO:954, SEQ ID NO: 960, SEQ ID NO: 966, SEQ ID NO: 972, SEQ ID NO: 978, SEQID NO: 984, SEQ ID NO: 990, SEQ ID NO: 996, SEQ ID NO: 1002, SEQ ID NO:1008, SEQ ID NO: 1014, SEQ ID NO: 1020, SEQ ID NO: 1026, SEQ ID NO:1032, SEQ ID NO: 1038, SEQ ID NO: 1044, SEQ ID NO: 1050, SEQ ID NO:1056, SEQ ID NO: 1062, SEQ ID NO: 1068, SEQ ID NO: 1074, SEQ ID NO:1080, SEQ ID NO: 1086, SEQ ID NO: 1092, SEQ ID NO: 1098, SEQ ID NO:1104, SEQ ID NO: 1110, SEQ ID NO: 1116, SEQ ID NO: 1122, SEQ ID NO:1128, SEQ ID NO: 1134, SEQ ID NO: 1140, SEQ ID NO: 1146, SEQ ID NO:1152, SEQ ID NO: 1158, SEQ ID NO: 1164, SEQ ID NO: 1170, SEQ ID NO:1176, SEQ ID NO: 1182, SEQ ID NO: 1188, SEQ ID NO: 1194, SEQ ID NO:1200, SEQ ID NO: 1206, SEQ ID NO: 1212, SEQ ID NO: 1218, SEQ ID NO:1224, SEQ ID NO: 1230, SEQ ID NO: 1236, SEQ ID NO: 1242, SEQ ID NO:1248, SEQ ID NO: 1254, SEQ ID NO: 1260, SEQ ID NO: 1266, SEQ ID NO:1272, SEQ ID NO: 1278, SEQ ID NO: 1284, SEQ ID NO: 1290, SEQ ID NO:1296, SEQ ID NO: 1302, SEQ ID NO: 1308, SEQ ID NO: 1314, SEQ ID NO:1320, SEQ ID NO: 1326, SEQ ID NO: 1332, SEQ ID NO: 1338, SEQ ID NO:1344, SEQ ID NO: 1350, SEQ ID NO: 1356, SEQ ID NO: 1362, SEQ ID NO:1368, SEQ ID NO: 1374, SEQ ID NO: 1380, SEQ ID NO: 1386, SEQ ID NO:1392, SEQ ID NO: 1398, SEQ ID NO: 1404, SEQ ID NO: 1410, SEQ ID NO:1416, SEQ ID NO: 1422, SEQ ID NO: 1428, SEQ ID NO: 1434, SEQ ID NO:1440, SEQ ID NO: 1446, SEQ ID NO: 1452, SEQ ID NO: 1458, SEQ ID NO:1464, SEQ ID NO: 1470, SEQ ID NO: 1476, SEQ ID NO: 1482, SEQ ID NO:1488, SEQ ID NO: 1494, SEQ ID NO: 1500, SEQ ID NO: 1506, SEQ ID NO:1512, SEQ ID NO: 1518, SEQ ID NO: 1524, SEQ ID NO: 1598, SEQ ID NO:1530, SEQ ID NO: 1536, SEQ ID NO: 1542, SEQ ID NO: 1548, SEQ ID NO:1554, SEQ ID NO: 1560, SEQ ID NO: 1566, SEQ ID NO: 1572, SEQ ID NO:1578, SEQ ID NO: 1584, or SEQ ID NO: 1590 in FIG. 3A, 3B, 3C, 3D, 3E,3F, 3G, 3H, 3I, 3J, 3K, or 3L, wherein the HCDR1, HCDR2, HCDR3, LCDR1,LCDR2, and LCDR3 are from a same clone.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain comprising the heavy chain aminoacid variable sequence in any one of SEQ ID NO. 1-SEQ ID NO: 97, SEQ IDNO: 195-SEQ ID NO: 209, or SEQ ID NO: 225-SEQ ID NO: 310 in FIG. 2A, 2B,2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a light chain comprising the light chain aminoacid variable sequence in any one of SEQ ID NO: 98-SEQ ID NO: 194, SEQID NO: 210-SEQ ID NO: 224, or SEQ ID NO: 311-SEQ ID NO: 396 in FIG. 2A,2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain comprising the heavy chain aminoacid variable sequence in any one of SEQ ID NO. 1-SEQ ID NO: 97, SEQ IDNO: 195-SEQ ID NO: 209, or SEQ ID NO: 225-SEQ ID NO: 310 in FIG. 2A, 2B,2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R and alight chain comprising the light chain amino acid variable sequence inany one of SEQ ID NO: 98-SEQ ID NO: 194, SEQ ID NO: 210-SEQ ID NO: 224,or SEQ ID NO: 311-SEQ ID NO: 396 in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H,2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises: a heavy chain CDR1 comprising SSYX₄MX₆ (SEQ IDNO: 1600) wherein X₄ is A, G, or S and X₆ is H, N, or S; a heavy chainCDR2 comprising WVY₃Y₄IY₆Y₇Y₈Y₉Y₁₀Y₁₁Y₁₂Y₁₃ (SEQ ID NO: 1601), whereinY₃ is S or A, Y₄ is G, N, S, Y, or A, Y₆ is S, K, or N, Y₇ is S, Y, orG, Y₈ is N or S, Y₉ is G, S, A, or T, Y₁₀ is G or S, Y₁₁ is S, N, or T,Y₁₂ is T, K, S, or I, Y₁₃ is S, Y, or G; and a heavy chain CDR3comprising ARZ₃PYZ₆Z₇WZ₉D (SEQ ID NO: 1602), wherein Z₃ is V, A, G, orE, Z₆ is S, D, or G, Z₇ is V or Y, Z₉ is I, A, M, or L.

In some embodiments, an isolated binding molecule that binds to humanTIGIT comprises at least one of: (a) (i) a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 23 and (ii) a lightchain variable region comprising the amino acid sequence of SEQ ID NO:120; (b) (i) a heavy chain variable region comprising the amino acidsequence of SEQ ID NO: 29 and (ii) a light chain variable regioncomprising the amino acid sequence of SEQ ID NO: 126; (c) (i) a heavychain variable region comprising the amino acid sequence of SEQ ID NO:45 and (ii) a light chain variable region comprising the amino acidsequence of SEQ ID NO: 142; (d) (i) a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 46 and (ii) a lightchain variable region comprising the amino acid sequence of SEQ ID NO:143; (e) (i) a heavy chain variable region comprising the amino acidsequence of SEQ ID NO: 58 and (ii) a light chain variable regioncomprising the amino acid sequence of SEQ ID NO: 155; (f) (i) a heavychain variable region comprising the amino acid sequence of SEQ ID NO:63 and (ii) a light chain variable region comprising the amino acidsequence of SEQ ID NO: 160; (g) (i) a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 67 and (ii) a lightchain variable region comprising the amino acid sequence of SEQ ID NO:164; (h) (i) a heavy chain variable region comprising the amino acidsequence of SEQ ID NO: 72 and (ii) a light chain variable regioncomprising the amino acid sequence of SEQ ID NO: 169; (i) (i) a heavychain variable region comprising the amino acid sequence of SEQ ID NO:80 and (ii) a light chain variable region comprising the amino acidsequence of SEQ ID NO: 177; or (j) (i) a heavy chain variable regionthat is at least 85% identical to any of the heavy chain variableregions in (a)-(i) and (ii) a light chain variable region that is atleast 85% identical to any of the light chain variable regions in(a)-(i).

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain CDR3 of contiguous amino acidsZ₁Z₂Z₃Z₄Z₅Z₆Z₇Z₈Z₉Z₁₀, (SEQ ID NO: 1599), wherein Z₁ is A; Z₂ is R; Z₃is E; Z₄ is P; Z₅ is Y; Z₆ is D, G, or S; Z₇ is V, Y, or T; Z₈ is W; Z₉is I, L, or M; and Z₁₀ is D.

In some embodiments, an isolated antibody comprises: (a) a heavy chainCDR1 comprising the amino acid sequence of any of one of the HCDR1s inSEQ ID NO: 397, SEQ ID NO: 403. SEQ ID NO: 409, SEQ ID NO: 415, SEQ IDNO: 421, SEQ ID NO: 427, SEQ ID NO: 433, SEQ ID NO: 439, SEQ ID NO: 445,SEQ ID NO: 451, SEQ ID NO: 457, SEQ ID NO: 463, SEQ ID NO: 469, SEQ IDNO: 475, SEQ ID NO: 481, SEQ ID NO: 487, SEQ ID NO: 493, SEQ ID NO: 499,SEQ ID NO: 505, SEQ ID NO: 511, SEQ ID NO: 517, SEQ ID NO: 523, SEQ IDNO: 529, SEQ ID NO: 535, SEQ ID NO: 541, SEQ ID NO: 547, SEQ ID NO: 553,SEQ ID NO: 559, SEQ ID NO: 565, SEQ ID NO: 571, SEQ ID NO: 577, SEQ IDNO: 583, SEQ ID NO: 589, SEQ ID NO: 595, SEQ ID NO: 601, SEQ ID NO: 607,SEQ ID NO: 613, SEQ ID NO: 619, SEQ ID NO: 625, SEQ ID NO: 631, SEQ IDNO: 637, SEQ ID NO: 643, SEQ ID NO: 649, SEQ ID NO: 655, SEQ ID NO: 661,SEQ ID NO: 667, SEQ ID NO: 673, SEQ ID NO: 679, SEQ ID NO: 685, SEQ IDNO: 691, SEQ ID NO: 697, SEQ ID NO: 703, SEQ ID NO: 709, SEQ ID NO: 715,SEQ ID NO: 721, SEQ ID NO: 727, SEQ ID NO: 733, SEQ ID NO: 739, SEQ IDNO: 745, SEQ ID NO: 751, SEQ ID NO: 757, SEQ ID NO: 763, SEQ ID NO: 769,SEQ ID NO: 775, SEQ ID NO: 781, SEQ ID NO: 787, SEQ ID NO: 793, SEQ IDNO: 799, SEQ ID NO: 805, SEQ ID NO: 811, SEQ ID NO: 817, SEQ ID NO: 823,SEQ ID NO: 829, SEQ ID NO: 835, SEQ ID NO: 841, SEQ ID NO: 847, SEQ IDNO: 853, SEQ ID NO: 859, SEQ ID NO: 865, SEQ ID NO: 871, SEQ ID NO: 877,SEQ ID NO: 883, SEQ ID NO: 889, SEQ ID NO: 895, SEQ ID NO: 901, SEQ IDNO: 907, SEQ ID NO: 913, SEQ ID NO: 919, SEQ ID NO: 925, SEQ ID NO: 931,SEQ ID NO: 937, SEQ ID NO: 943, SEQ ID NO: 949, SEQ ID NO: 955, SEQ IDNO: 961, SEQ ID NO: 967, SEQ ID NO: 973, SEQ ID NO: 979, SEQ ID NO: 985,SEQ ID NO: 991, SEQ ID NO: 997, SEQ ID NO: 1003, SEQ ID NO: 1009, SEQ IDNO: 1015, SEQ ID NO: 1021, SEQ ID NO: 1027, SEQ ID NO: 1033, SEQ ID NO:1039, SEQ ID NO: 1045, SEQ ID NO: 1051, SEQ ID NO: 1057, SEQ ID NO:1063, SEQ ID NO: 1069, SEQ ID NO: 1075, SEQ ID NO: 1081, SEQ ID NO:1087, SEQ ID NO: 1093, SEQ ID NO: 1099, SEQ ID NO: 1105, SEQ ID NO:1111, SEQ ID NO: 1117, SEQ ID NO: 1123, SEQ ID NO: 1129, SEQ ID NO:1135, SEQ ID NO: 1141, SEQ ID NO: 1147, SEQ ID NO: 1153, SEQ ID NO:1159, SEQ ID NO: 1165, SEQ ID NO: 1171, SEQ ID NO: 1177, SEQ ID NO:1183, SEQ ID NO: 1189, SEQ ID NO: 1195, SEQ ID NO: 1201, SEQ ID NO:1207, SEQ ID NO: 1213, SEQ ID NO: 1219, SEQ ID NO: 1225, SEQ ID NO:1231, SEQ ID NO: 1237, SEQ ID NO: 1243, SEQ ID NO: 1249, SEQ ID NO:1255, SEQ ID NO: 1261, SEQ ID NO: 1267, SEQ ID NO: 1273, SEQ ID NO:1279, SEQ ID NO: 1285, SEQ ID NO: 1291, SEQ ID NO: 1297, SEQ ID NO:1303, SEQ ID NO: 1309, SEQ ID NO: 1315, SEQ ID NO: 1321, SEQ ID NO:1327, SEQ ID NO: 1333, SEQ ID NO: 1339, SEQ ID NO: 1345, SEQ ID NO:1351, SEQ ID NO: 1357, SEQ ID NO: 1363, SEQ ID NO: 1369, SEQ ID NO:1375, SEQ ID NO: 1381, SEQ ID NO: 1387, SEQ ID NO: 1393, SEQ ID NO:1399, SEQ ID NO: 1405, SEQ ID NO: 1411, SEQ ID NO: 1417, SEQ ID NO:1423, SEQ ID NO: 1429, SEQ ID NO: 1435, SEQ ID NO: 1441, SEQ ID NO:1447, SEQ ID NO: 1453, SEQ ID NO: 1459, SEQ ID NO: 1465, SEQ ID NO:1471, SEQ ID NO: 1477, SEQ ID NO: 1483, SEQ ID NO: 1489, SEQ ID NO:1495, SEQ ID NO: 1501, SEQ ID NO: 1507, SEQ ID NO: 1513, SEQ ID NO:1519, SEQ ID NO: 1593, SEQ ID NO: 1525 SEQ ID NO: 1531, SEQ ID NO: 1537,SEQ ID NO: 1543, SEQ ID NO: 1549, SEQ ID NO: 1555, SEQ ID NO: 1561, SEQID NO: 1567, SEQ ID NO: 1573, SEQ ID NO: 1579, or SEQ ID NO: 1585 inFIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L; (b) a heavychain CDR2 comprising the amino acid sequence of any one of the HCDR2sin in SEQ ID NO: 398, SEQ ID NO: 404, SEQ ID NO: 410, SEQ ID NO: 416,SEQ ID NO: 422, SEQ ID NO: 428, SEQ ID NO: 434, SEQ ID NO: 440, SEQ IDNO: 446, SEQ ID NO: 452, SEQ ID NO: 458, SEQ ID NO: 464, SEQ ID NO: 470,SEQ ID NO: 476, SEQ ID NO: 482, SEQ ID NO: 488, SEQ ID NO: 494, SEQ IDNO: 500, SEQ ID NO: 506, SEQ ID NO: 512, SEQ ID NO: 518, SEQ ID NO: 524,SEQ ID NO: 530, SEQ ID NO: 536, SEQ ID NO: 542, SEQ ID NO: 548, SEQ IDNO: 554, SEQ ID NO: 560, SEQ ID NO: 566, SEQ ID NO: 572, SEQ ID NO: 578,SEQ ID NO: 584, SEQ ID NO: 590, SEQ ID NO: 596, SEQ ID NO: 602, SEQ IDNO: 608, SEQ ID NO: 614, SEQ ID NO: 620, SEQ ID NO: 626, SEQ ID NO: 632,SEQ ID NO: 638, SEQ ID NO: 644, SEQ ID NO: 650, SEQ ID NO: 656, SEQ IDNO: 662, SEQ ID NO: 668, SEQ ID NO: 674, SEQ ID NO: 680, SEQ ID NO: 686,SEQ ID NO: 692, SEQ ID NO: 698, SEQ ID NO: 704, SEQ ID NO: 710, SEQ IDNO: 716, SEQ ID NO: 722, SEQ ID NO: 728, SEQ ID NO: 734, SEQ ID NO: 740,SEQ ID NO: 746, SEQ ID NO: 752, SEQ ID NO: 758, SEQ ID NO: 764, SEQ IDNO: 770, SEQ ID NO: 776, SEQ ID NO: 782, SEQ ID NO: 788, SEQ ID NO: 794,SEQ ID NO: 800, SEQ ID NO: 806, SEQ ID NO: 812, SEQ ID NO: 818, SEQ IDNO: 824, SEQ ID NO: 830, SEQ ID NO: 836, SEQ ID NO: 842, SEQ ID NO: 848,SEQ ID NO: 854, SEQ ID NO: 860, SEQ ID NO: 866, SEQ ID NO: 872, SEQ IDNO: 878, SEQ ID NO: 884, SEQ ID NO: 890, SEQ ID NO: 896, SEQ ID NO: 902,SEQ ID NO: 908, SEQ ID NO: 914, SEQ ID NO: 920, SEQ ID NO: 926, SEQ IDNO: 932, SEQ ID NO: 938, SEQ ID NO: 944, SEQ ID NO: 950, SEQ ID NO: 956,SEQ ID NO: 962, SEQ ID NO: 968, SEQ ID NO: 974, SEQ ID NO: 980, SEQ IDNO: 986, SEQ ID NO: 992, SEQ ID NO: 998, SEQ ID NO: 1004, SEQ ID NO:1010, SEQ ID NO: 1016, SEQ ID NO: 1022, SEQ ID NO: 1028, SEQ ID NO:1034, SEQ ID NO: 1040, SEQ ID NO: 1046, SEQ ID NO: 1052, SEQ ID NO:1058, SEQ ID NO: 1064, SEQ ID NO: 1070, SEQ ID NO: 1076, SEQ ID NO:1082, SEQ ID NO: 1088, SEQ ID NO: 1094, SEQ ID NO: 1100, SEQ ID NO:1106, SEQ ID NO: 1112, SEQ ID NO: 1118, SEQ ID NO: 1124, SEQ ID NO:1130, SEQ ID NO: 1136, SEQ ID NO: 1142, SEQ ID NO: 1148, SEQ ID NO:1154, SEQ ID NO: 1160, SEQ ID NO: 1166, SEQ ID NO: 1172, SEQ ID NO:1178, SEQ ID NO: 1184, SEQ ID NO: 1190, SEQ ID NO: 1196, SEQ ID NO:1202, SEQ ID NO: 1208, SEQ ID NO: 1214, SEQ ID NO: 1220, SEQ ID NO:1226, SEQ ID NO: 1232, SEQ ID NO: 1238, SEQ ID NO: 1244, SEQ ID NO:1250, SEQ ID NO: 1256, SEQ ID NO: 1262, SEQ ID NO: 1268, SEQ ID NO:1274, SEQ ID NO: 1280, SEQ ID NO: 1286, SEQ ID NO: 1292, SEQ ID NO:1298, SEQ ID NO: 1304, SEQ ID NO: 1310, SEQ ID NO: 1316, SEQ ID NO:1322, SEQ ID NO: 1328, SEQ ID NO: 1334, SEQ ID NO: 1340, SEQ ID NO:1346, SEQ ID NO: 1352, SEQ ID NO: 1358, SEQ ID NO: 1364, SEQ ID NO:1370, SEQ ID NO: 1376, SEQ ID NO: 1382, SEQ ID NO: 1388, SEQ ID NO:1394, SEQ ID NO: 1400, SEQ ID NO: 1406, SEQ ID NO: 1412, SEQ ID NO:1418, SEQ ID NO: 1424, SEQ ID NO: 1430, SEQ ID NO: 1436, SEQ ID NO:1442, SEQ ID NO: 1448, SEQ ID NO: 1454, SEQ ID NO: 1460, SEQ ID NO:1466, SEQ ID NO: 1472, SEQ ID NO: 1478, SEQ ID NO: 1484, SEQ ID NO:1490, SEQ ID NO: 1496, SEQ ID NO: 1502, SEQ ID NO: 1508, SEQ ID NO:1514, SEQ ID NO: 1520, SEQ ID NO: 1594, SEQ ID NO: 1526, SEQ ID NO:1532, SEQ ID NO: 1538, SEQ ID NO: 1544, SEQ ID NO: 1550, SEQ ID NO:1556, SEQ ID NO: 1562, SEQ ID NO: 1568, SEQ ID NO: 1574, SEQ ID NO:1580, or SEQ ID NO: 1586 in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J,3K, or 3L; (c) a heavy chain CDR3 comprising the amino acid sequence ofany one of the HCDR3s in SEQ ID NO: 399, SEQ ID NO: 405, SEQ ID NO: 411,SEQ ID NO: 417, SEQ ID NO: 423, SEQ ID NO: 429, SEQ ID NO: 435, SEQ IDNO: 441, SEQ ID NO: 447, SEQ ID NO: 453, SEQ ID NO: 459, SEQ ID NO: 465,SEQ ID NO: 471, SEQ ID NO: 477, SEQ ID NO: 483, SEQ ID NO: 489, SEQ IDNO: 495, SEQ ID NO: 501, SEQ ID NO: 507, SEQ ID NO: 513, SEQ ID NO: 519,SEQ ID NO: 525, SEQ ID NO: 531, SEQ ID NO: 537, SEQ ID NO: 543, SEQ IDNO: 549, SEQ ID NO: 555, SEQ ID NO: 561, SEQ ID NO: 567, SEQ ID NO: 573,SEQ ID NO: 579, SEQ ID NO: 585, SEQ ID NO: 591, SEQ ID NO: 597, SEQ IDNO: 603, SEQ ID NO: 609, SEQ ID NO: 615, SEQ ID NO: 621, SEQ ID NO: 627,SEQ ID NO: 633, SEQ ID NO: 639, SEQ ID NO: 645, SEQ ID NO: 651, SEQ IDNO: 657, SEQ ID NO: 663, SEQ ID NO: 669, SEQ ID NO: 675, SEQ ID NO: 681,SEQ ID NO: 687, SEQ ID NO: 693, SEQ ID NO: 699, SEQ ID NO: 705, SEQ IDNO: 711, SEQ ID NO: 717, SEQ ID NO: 723, SEQ ID NO: 729, SEQ ID NO: 735,SEQ ID NO: 741, SEQ ID NO: 747, SEQ ID NO: 753, SEQ ID NO: 759, SEQ IDNO: 765, SEQ ID NO: 771, SEQ ID NO: 777, SEQ ID NO: 783, SEQ ID NO: 789,SEQ ID NO: 795, SEQ ID NO: 801, SEQ ID NO: 807, SEQ ID NO: 813, SEQ IDNO: 819, SEQ ID NO: 825, SEQ ID NO: 831, SEQ ID NO: 837, SEQ ID NO: 843,SEQ ID NO: 849, SEQ ID NO: 855, SEQ ID NO: 861, SEQ ID NO: 867, SEQ IDNO: 873, SEQ ID NO: 879, SEQ ID NO: 885, SEQ ID NO: 891, SEQ ID NO: 897,SEQ ID NO: 903, SEQ ID NO: 909, SEQ ID NO: 915, SEQ ID NO: 921, SEQ IDNO: 927, SEQ ID NO: 933, SEQ ID NO: 939, SEQ ID NO: 945, SEQ ID NO: 951,SEQ ID NO: 957, SEQ ID NO: 963, SEQ ID NO: 969, SEQ ID NO: 975, SEQ IDNO: 981, SEQ ID NO: 987, SEQ ID NO: 993, SEQ ID NO: 999, SEQ ID NO:1005, SEQ ID NO: 1011, SEQ ID NO: 1017, SEQ ID NO: 1023, SEQ ID NO:1029, SEQ ID NO: 1035, SEQ ID NO: 1041, SEQ ID NO: 1047, SEQ ID NO:1053, SEQ ID NO: 1059, SEQ ID NO: 1065, SEQ ID NO: 1071, SEQ ID NO:1077, SEQ ID NO: 1083, SEQ ID NO: 1089, SEQ ID NO: 1095, SEQ ID NO:1101, SEQ ID NO: 1107, SEQ ID NO: 1113, SEQ ID NO: 1119, SEQ ID NO:1125, SEQ ID NO: 1131, SEQ ID NO: 1137, SEQ ID NO: 1143, SEQ ID NO:1149, SEQ ID NO: 1155, SEQ ID NO: 1161, SEQ ID NO: 1167, SEQ ID NO:1173, SEQ ID NO: 1179, SEQ ID NO: 1185, SEQ ID NO: 1191, SEQ ID NO:1197, SEQ ID NO: 1203, SEQ ID NO: 1209, SEQ ID NO: 1215, SEQ ID NO:1221, SEQ ID NO: 1227, SEQ ID NO: 1233, SEQ ID NO: 1239, SEQ ID NO:1245, SEQ ID NO: 1251, SEQ ID NO: 1257, SEQ ID NO: 1263, SEQ ID NO:1269, SEQ ID NO: 1275, SEQ ID NO: 1281, SEQ ID NO: 1287, SEQ ID NO:1293, SEQ ID NO: 1299, SEQ ID NO: 1305, SEQ ID NO: 1311, SEQ ID NO:1317, SEQ ID NO: 1323, SEQ ID NO: 1329, SEQ ID NO: 1335, SEQ ID NO:1341, SEQ ID NO: 1347, SEQ ID NO: 1353, SEQ ID NO: 1359, SEQ ID NO:1365, SEQ ID NO: 1371, SEQ ID NO: 1377, SEQ ID NO: 1383, SEQ ID NO:1389, SEQ ID NO: 1395, SEQ ID NO: 1401, SEQ ID NO: 1407, SEQ ID NO:1413, SEQ ID NO: 1419, SEQ ID NO: 1425, SEQ ID NO: 1431, SEQ ID NO:1437, SEQ ID NO: 1443, SEQ ID NO: 1449, SEQ ID NO: 1455, SEQ ID NO:1461, SEQ ID NO: 1467, SEQ ID NO: 1473, SEQ ID NO: 1479, SEQ ID NO:1485, SEQ ID NO: 1491, SEQ ID NO: 1497, SEQ ID NO: 1503, SEQ ID NO:1509, SEQ ID NO: 1515, SEQ ID NO: 1521, SEQ ID NO: 1595, SEQ ID NO:1527, SEQ ID NO: 1533, SEQ ID NO: 1539, SEQ ID NO: 1545, SEQ ID NO:1551, SEQ ID NO: 1557, SEQ ID NO: 1563, SEQ ID NO: 1569, SEQ ID NO:1575, SEQ ID NO: 1581, or SEQ ID NO: 1587 in FIG. 3A, 3B, 3C, 3D, 3E,3F, 3G, 3H, 3I, 3J, 3K, or 3L; (d) a light chain CDR1 comprising theamino acid sequence of any one of the LCDR1s in SEQ ID NO: 400, SEQ IDNO: 406, SEQ ID NO: 412, SEQ ID NO: 418, SEQ ID NO: 424, SEQ ID NO: 430,SEQ ID NO: 436, SEQ ID NO: 442, SEQ ID NO: 448, SEQ ID NO: 454, SEQ IDNO: 460, SEQ ID NO: 466, SEQ ID NO: 472, SEQ ID NO: 478, SEQ ID NO: 484,SEQ ID NO: 490, SEQ ID NO: 496, SEQ ID NO: 502, SEQ ID NO: 508, SEQ IDNO: 514, SEQ ID NO: 520, SEQ ID NO: 526, SEQ ID NO: 532, SEQ ID NO: 538,SEQ ID NO: 544, SEQ ID NO: 550, SEQ ID NO: 556, SEQ ID NO: 562, SEQ IDNO: 568, SEQ ID NO: 574, SEQ ID NO: 580, SEQ ID NO: 586, SEQ ID NO: 592,SEQ ID NO: 598, SEQ ID NO: 604, SEQ ID NO: 610, SEQ ID NO: 616, SEQ IDNO: 622, SEQ ID NO: 628, SEQ ID NO: 634, SEQ ID NO: 640, SEQ ID NO: 646,SEQ ID NO: 652, SEQ ID NO: 658, SEQ ID NO: 664, SEQ ID NO: 670, SEQ IDNO: 676, SEQ ID NO: 682, SEQ ID NO: 688, SEQ ID NO: 694, SEQ ID NO: 700,SEQ ID NO: 706, SEQ ID NO: 712, SEQ ID NO: 718, SEQ ID NO: 724, SEQ IDNO: 730, SEQ ID NO: 736, SEQ ID NO: 742, SEQ ID NO: 748, SEQ ID NO: 754,SEQ ID NO: 760, SEQ ID NO: 766, SEQ ID NO: 772, SEQ ID NO: 778, SEQ IDNO: 784, SEQ ID NO: 790, SEQ ID NO: 796, SEQ ID NO: 802, SEQ ID NO: 808,SEQ ID NO: 814, SEQ ID NO: 820, SEQ ID NO: 826, SEQ ID NO: 832, SEQ IDNO: 838, SEQ ID NO: 844, SEQ ID NO: 850, SEQ ID NO: 856, SEQ ID NO: 862,SEQ ID NO: 868, SEQ ID NO: 874, SEQ ID NO: 880, SEQ ID NO: 886, SEQ IDNO: 892, SEQ ID NO: 898, SEQ ID NO: 904, SEQ ID NO: 910, SEQ ID NO: 916,SEQ ID NO: 922, SEQ ID NO: 928, SEQ ID NO: 934, SEQ ID NO: 940, SEQ IDNO: 946, SEQ ID NO: 952, SEQ ID NO: 958, SEQ ID NO: 964, SEQ ID NO: 970,SEQ ID NO: 976, SEQ ID NO: 982, SEQ ID NO: 988, SEQ ID NO: 994, SEQ IDNO: 1000, SEQ ID NO: 1006, SEQ ID NO: 1012, SEQ ID NO: 1018, SEQ ID NO:1024, SEQ ID NO: 1030, SEQ ID NO: 1036, SEQ ID NO: 1042, SEQ ID NO:1048, SEQ ID NO: 1054, SEQ ID NO: 1060, SEQ ID NO: 1066, SEQ ID NO:1072, SEQ ID NO: 1078, SEQ ID NO: 1084, SEQ ID NO: 1090, SEQ ID NO:1096, SEQ ID NO: 1102, SEQ ID NO: 1108, SEQ ID NO: 1114, SEQ ID NO:1120, SEQ ID NO: 1126, SEQ ID NO: 1132, SEQ ID NO: 1138, SEQ ID NO:1144, SEQ ID NO: 1150, SEQ ID NO: 1156, SEQ ID NO: 1162, SEQ ID NO:1168, SEQ ID NO: 1174, SEQ ID NO: 1180, SEQ ID NO: 1186, SEQ ID NO:1192, SEQ ID NO: 1198, SEQ ID NO: 1204, SEQ ID NO: 1210, SEQ ID NO:1216, SEQ ID NO: 1222, SEQ ID NO: 1228, SEQ ID NO: 1234, SEQ ID NO:1240, SEQ ID NO: 1246, SEQ ID NO: 1252, SEQ ID NO: 1258, SEQ ID NO:1264, SEQ ID NO: 1270, SEQ ID NO: 1276, SEQ ID NO: 1282, SEQ ID NO:1288, SEQ ID NO: 1294, SEQ ID NO: 1300, SEQ ID NO: 1306, SEQ ID NO:1312, SEQ ID NO: 1318, SEQ ID NO: 1324, SEQ ID NO: 1330, SEQ ID NO:1336, SEQ ID NO: 1342, SEQ ID NO: 1348, SEQ ID NO: 1354, SEQ ID NO:1360, SEQ ID NO: 1366, SEQ ID NO: 1372, SEQ ID NO: 1378, SEQ ID NO:1384, SEQ ID NO: 1390, SEQ ID NO: 1396, SEQ ID NO: 1402, SEQ ID NO:1408, SEQ ID NO: 1414, SEQ ID NO: 1420, SEQ ID NO: 1426, SEQ ID NO:1432, SEQ ID NO: 1438, SEQ ID NO: 1444, SEQ ID NO: 1450. SEQ ID NO:1456, SEQ ID NO: 1462, SEQ ID NO: 1468, SEQ ID NO: 1474, SEQ ID NO:1480, SEQ ID NO: 1486, SEQ ID NO: 1492, SEQ ID NO: 1498, SEQ ID NO:1504, SEQ ID NO: 1510, SEQ ID NO: 1516, SEQ ID NO: 1522, SEQ ID NO:1596, SEQ ID NO: 1528, SEQ ID NO: 1534, SEQ ID NO: 1540, SEQ ID NO:1546, SEQ ID NO: 1552, SEQ ID NO: 1558, SEQ ID NO: 1564, SEQ ID NO:1570, SEQ ID NO: 1576, SEQ ID NO: 1582, or SEQ ID NO: 1588 in FIG. 3A,3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L; (e) a light chain CDR2comprising the amino acid sequence of any one of the LCDR2s in SEQ IDNO: 401, SEQ ID NO: 407, SEQ ID NO: 413, SEQ ID NO: 419, SEQ ID NO: 425,SEQ ID NO: 431, SEQ ID NO: 437, SEQ ID NO: 443, SEQ ID NO: 449, SEQ IDNO: 455, SEQ ID NO: 461, SEQ ID NO: 467, SEQ ID NO: 473, SEQ ID NO: 479,SEQ ID NO: 485, SEQ ID NO: 491, SEQ ID NO: 497, SEQ ID NO: 503, SEQ IDNO: 509, SEQ ID NO: 515, SEQ ID NO: 521, SEQ ID NO: 527, SEQ ID NO: 533,SEQ ID NO: 539, SEQ ID NO: 545, SEQ ID NO: 551, SEQ ID NO: 557, SEQ IDNO: 563, SEQ ID NO: 569, SEQ ID NO: 575, SEQ ID NO: 581, SEQ ID NO: 587,SEQ ID NO: 593, SEQ ID NO: 599, SEQ ID NO: 605, SEQ ID NO: 611, SEQ IDNO: 617, SEQ ID NO: 623, SEQ ID NO: 629, SEQ ID NO: 635, SEQ ID NO: 641,SEQ ID NO: 647, SEQ ID NO: 653, SEQ ID NO: 659, SEQ ID NO: 665, SEQ IDNO: 671, SEQ ID NO: 677, SEQ ID NO: 683, SEQ ID NO: 689, SEQ ID NO: 695,SEQ ID NO: 701, SEQ ID NO: 707, SEQ ID NO: 713, SEQ ID NO: 719, SEQ IDNO: 725, SEQ ID NO: 731, SEQ ID NO: 737, SEQ ID NO: 743, SEQ ID NO: 749,SEQ ID NO: 755, SEQ ID NO: 761, SEQ ID NO: 767, SEQ ID NO: 773, SEQ IDNO: 779, SEQ ID NO: 785, SEQ ID NO: 791, SEQ ID NO: 797, SEQ ID NO: 803,SEQ ID NO: 809, SEQ ID NO: 815, SEQ ID NO: 821, SEQ ID NO: 827, SEQ IDNO: 833, SEQ ID NO: 839, SEQ ID NO: 845, SEQ ID NO: 851, SEQ ID NO: 857,SEQ ID NO: 863, SEQ ID NO: 869, SEQ ID NO: 875, SEQ ID NO: 881, SEQ IDNO: 887, SEQ ID NO: 893, SEQ ID NO: 899, SEQ ID NO: 905, SEQ ID NO: 911,SEQ ID NO: 917, SEQ ID NO: 923, SEQ ID NO: 929, SEQ ID NO: 935, SEQ IDNO: 941, SEQ ID NO: 947, SEQ ID NO: 953, SEQ ID NO: 959, SEQ ID NO: 965,SEQ ID NO: 971, SEQ ID NO: 977, SEQ ID NO: 983, SEQ ID NO: 989, SEQ IDNO: 995, SEQ ID NO: 1001, SEQ ID NO: 1007, SEQ ID NO: 1013, SEQ ID NO:1019, SEQ ID NO: 1025, SEQ ID NO: 1031, SEQ ID NO: 1037, SEQ ID NO:1043, SEQ ID NO: 1049, SEQ ID NO: 1055, SEQ ID NO: 1061, SEQ ID NO:1067, SEQ ID NO: 1073, SEQ ID NO: 1079, SEQ ID NO: 1085, SEQ ID NO:1091, SEQ ID NO: 1097, SEQ ID NO: 1103, SEQ ID NO: 1109, SEQ ID NO:1115, SEQ ID NO: 1121, SEQ ID NO: 1127, SEQ ID NO: 1133, SEQ ID NO:1139, SEQ ID NO: 1145, SEQ ID NO: 1151, SEQ ID NO: 1157, SEQ ID NO:1163, SEQ ID NO: 1169, SEQ ID NO: 1175, SEQ ID NO: 1181, SEQ ID NO:1187, SEQ ID NO: 1193, SEQ ID NO: 1199, SEQ ID NO: 1205, SEQ ID NO:1211, SEQ ID NO: 1217, SEQ ID NO: 1223, SEQ ID NO: 1229, SEQ ID NO:1235, SEQ ID NO: 1241, SEQ ID NO: 1247, SEQ ID NO: 1253, SEQ ID NO:1259, SEQ ID NO: 1265, SEQ ID NO: 1271, SEQ ID NO: 1277, SEQ ID NO:1283, SEQ ID NO: 1289, SEQ ID NO: 1295, SEQ ID NO: 1301, SEQ ID NO:1307, SEQ ID NO: 1313, SEQ ID NO: 1319, SEQ ID NO: 1325, SEQ ID NO:1331, SEQ ID NO: 1337, SEQ ID NO: 1343, SEQ ID NO: 1349, SEQ ID NO:1355, SEQ ID NO: 1361, SEQ ID NO: 1367, SEQ ID NO: 1373, SEQ ID NO:1379, SEQ ID NO: 1385, SEQ ID NO: 1391, SEQ ID NO: 1397, SEQ ID NO:1403, SEQ ID NO: 1409, SEQ ID NO: 1415, SEQ ID NO: 1421, SEQ ID NO:1427, SEQ ID NO: 1433, SEQ ID NO: 1439, SEQ ID NO: 1445, SEQ ID NO:1451, SEQ ID NO: 1457, SEQ ID NO: 1463, SEQ ID NO: 1469, SEQ ID NO:1475, SEQ ID NO: 1481, SEQ ID NO: 1487, SEQ ID NO: 1493, SEQ ID NO:1499, SEQ ID NO: 1505, SEQ ID NO: 1511, SEQ ID NO: 1517, SEQ ID NO:1523, SEQ ID NO: 1597, SEQ ID NO: 1529, SEQ ID NO: 1535, SEQ ID NO:1541, SEQ ID NO: 1547, SEQ ID NO: 1553, SEQ ID NO: 1559, SEQ ID NO:1565, SEQ ID NO: 1571, SEQ ID NO: 1577, SEQ ID NO: 1583, or SEQ ID NO:1589 in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L; and (f)a light chain CDR3 comprising the amino acid sequence of any one of theLCDR3s in SEQ ID NO: 402, SEQ ID NO: 408, SEQ ID NO: 414, SEQ ID NO:420, SEQ ID NO: 426, SEQ ID NO: 432, SEQ ID NO: 438, SEQ ID NO: 444, SEQID NO: 450, SEQ ID NO: 456, SEQ ID NO: 462, SEQ ID NO: 468, SEQ ID NO:474, SEQ ID NO: 480, SEQ ID NO: 486, SEQ ID NO: 492, SEQ ID NO: 498, SEQID NO: 504, SEQ ID NO: 510, SEQ ID NO: 516, SEQ ID NO: 522, SEQ ID NO:528, SEQ ID NO: 534, SEQ ID NO: 540, SEQ ID NO: 546, SEQ ID NO: 552, SEQID NO: 558, SEQ ID NO: 564, SEQ ID NO: 570, SEQ ID NO: 576, SEQ ID NO:582, SEQ ID NO: 588, SEQ ID NO: 594, SEQ ID NO: 600, SEQ ID NO: 606, SEQID NO: 612, SEQ ID NO: 618, SEQ ID NO: 624, SEQ ID NO: 630, SEQ ID NO:636, SEQ ID NO: 642, SEQ ID NO: 648, SEQ ID NO: 654, SEQ ID NO: 660, SEQID NO: 666, SEQ ID NO: 672, SEQ ID NO: 678, SEQ ID NO: 684, SEQ ID NO:690, SEQ ID NO: 696, SEQ ID NO: 702, SEQ ID NO: 708, SEQ ID NO: 714, SEQID NO: 720, SEQ ID NO: 726, SEQ ID NO: 732, SEQ ID NO: 738, SEQ ID NO:744, SEQ ID NO: 750, SEQ ID NO: 756, SEQ ID NO: 762, SEQ ID NO: 768, SEQID NO: 774, SEQ ID NO: 780, SEQ ID NO: 786, SEQ ID NO: 792, SEQ ID NO:798, SEQ ID NO: 804, SEQ ID NO: 810, SEQ ID NO: 816, SEQ ID NO: 822, SEQID NO: 828, SEQ ID NO: 834, SEQ ID NO: 840, SEQ ID NO: 846, SEQ ID NO:852, SEQ ID NO: 858, SEQ ID NO: 864, SEQ ID NO: 870, SEQ ID NO: 876, SEQID NO: 882, SEQ ID NO: 888, SEQ ID NO: 894, SEQ ID NO: 900, SEQ ID NO:906, SEQ ID NO: 912, SEQ ID NO: 918, SEQ ID NO: 924, SEQ ID NO: 930, SEQID NO: 936, SEQ ID NO: 942, SEQ ID NO: 948, SEQ ID NO: 954, SEQ ID NO:960, SEQ ID NO: 966, SEQ ID NO: 972, SEQ ID NO: 978, SEQ ID NO: 984, SEQID NO: 990, SEQ ID NO: 996, SEQ ID NO: 1002, SEQ ID NO: 1008, SEQ ID NO:1014, SEQ ID NO: 1020, SEQ ID NO: 1026, SEQ ID NO: 1032, SEQ ID NO:1038, SEQ ID NO: 1044, SEQ ID NO: 1050, SEQ ID NO: 1056, SEQ ID NO:1062, SEQ ID NO: 1068, SEQ ID NO: 1074, SEQ ID NO: 1080, SEQ ID NO:1086, SEQ ID NO: 1092, SEQ ID NO: 1098, SEQ ID NO: 1104, SEQ ID NO:1110, SEQ ID NO: 1116, SEQ ID NO: 1122, SEQ ID NO: 1128, SEQ ID NO:1134, SEQ ID NO: 1140, SEQ ID NO: 1146, SEQ ID NO: 1152, SEQ ID NO:1158, SEQ ID NO: 1164, SEQ ID NO: 1170, SEQ ID NO: 1176, SEQ ID NO:1182, SEQ ID NO: 1188, SEQ ID NO: 1194, SEQ ID NO: 1200, SEQ ID NO:1206, SEQ ID NO: 1212, SEQ ID NO: 1218, SEQ ID NO: 1224, SEQ ID NO:1230, SEQ ID NO: 1236, SEQ ID NO: 1242, SEQ ID NO: 1248, SEQ ID NO:1254, SEQ ID NO: 1260, SEQ ID NO: 1266, SEQ ID NO: 1272, SEQ ID NO:1278, SEQ ID NO: 1284, SEQ ID NO: 1290, SEQ ID NO: 1296, SEQ ID NO:1302, SEQ ID NO: 1308, SEQ ID NO: 1314, SEQ ID NO: 1320, SEQ ID NO:1326, SEQ ID NO: 1332, SEQ ID NO: 1338, SEQ ID NO: 1344, SEQ ID NO:1350, SEQ ID NO: 1356, SEQ ID NO: 1362, SEQ ID NO: 1368, SEQ ID NO:1374, SEQ ID NO: 1380, SEQ ID NO: 1386, SEQ ID NO: 1392, SEQ ID NO:1398, SEQ ID NO: 1404, SEQ ID NO: 1410, SEQ ID NO: 1416, SEQ ID NO:1422, SEQ ID NO: 1428, SEQ ID NO: 1434, SEQ ID NO: 1440, SEQ ID NO:1446, SEQ ID NO: 1452, SEQ ID NO: 1458, SEQ ID NO: 1464, SEQ ID NO:1470, SEQ ID NO: 1476, SEQ ID NO: 1482, SEQ ID NO: 1488, SEQ ID NO:1494, SEQ ID NO: 1500, SEQ ID NO: 1506, SEQ ID NO: 1512, SEQ ID NO:1518, SEQ ID NO: 1524, SEQ ID NO: 1598, SEQ ID NO: 1530, SEQ ID NO:1536, SEQ ID NO: 1542, SEQ ID NO: 1548, SEQ ID NO: 1554, SEQ ID NO:1560, SEQ ID NO: 1566, SEQ ID NO: 1572, SEQ ID NO: 1578, SEQ ID NO:1584, or SEQ ID NO: 1590 in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J,3K, or 3L, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 arefrom a same clone.

In some embodiments, an isolated antibody comprises a heavy chaincomprising the heavy chain amino acid variable sequence in any one ofSEQ ID NO. 1-SEQ ID NO: 97, SEQ ID NO: 195-SEQ ID NO: 209, or SEQ ID NO:225-SEQ ID NO: 310 in FIG. 2A, 2B, or 2C, or a sequence at least 90%identical thereto.

In some embodiments, an isolated antibody comprises a light chaincomprising the light chain amino acid variable sequence in any one ofSEQ ID NO: 98-SEQ ID NO: 194, SEQ ID NO: 210-SEQ ID NO: 224, or SEQ IDNO: 311-SEQ ID NO: 396 in FIG. 2A, 2B, or 2C, or a sequence at least 90%identical thereto.

In some embodiments, an isolated antibody comprises a heavy chaincomprising the heavy chain amino acid variable sequence in any one ofSEQ ID NO. 1-SEQ ID NO: 97, SEQ ID NO: 195-SEQ ID NO: 209, or SEQ ID NO:225-SEQ ID NO: 310 in FIG. 2A, 2B, or 2C, or a sequence at least 90%identical thereto, and a light chain comprising the light chain aminoacid variable sequence in any one of SEQ ID NO: 98-SEQ ID NO: 194, SEQID NO: 210-SEQ ID NO: 224, or SEQ ID NO: 311-SEQ ID NO: 396 in FIG. 2A,2B, or 2C or a sequence at least 90% identical thereto.

In some embodiments, a composition comprises an isolated antigen bindingmolecule or antibody provided herein in an amount that ispharmaceutically acceptable, and a pharmaceutically acceptable carrier.

In some embodiments, a method of treating a TIGIT related disordercomprises identifying a subject with a TIGIT related disorder, andadministering an effective dose of the isolated antigen binding moleculeor antibody provided herein to the subject.

In some embodiments, a method of enhancing T-cell activation comprisesdiagnosing an individual with low T-cell counts, and administering aneffective dose of the isolated antigen binding molecule or isolatedantibody provided herein.

In some embodiments, a method of making an isolated antigen bindingmolecule that binds to human TIGIT comprises providing a nucleic acidthat encodes for the isolated antigen binding molecule or isolatedantibody provided herein, and expressing a protein encoded by thenucleic acid.

In some embodiments, a kit for determining the presence of human TIGITcomprises the isolated antigen binding molecule or isolated antibodyprovided herein, and a detectable marker.

In some embodiments, a method of preventing, treating and/or lesseningthe severity of an immune-related disease relating to aberrant immunecell response in a subject comprises modulating the activity of TIGIT inthe subject by administering an effective amount of any one or more ofthe isolated antigen binding molecules or antibodies provided herein.

In some embodiments, disclosed herein is a method of increasing orstimulating an immune response by administering in vitro or in vivo anantagonist of TIGIT activity, and/or by inhibiting intracellularsignaling mediated by TIGIT binding to PVR (aka CD155), wherein theantagonist of TIGIT activity is any one or more of the isolated antigenbinding molecules or isolated antibodies provided herein.

In some embodiments, a method of increasing T cell activation comprisesadministering any one or more of the isolated antigen binding moleculesor isolated antibodies provided herein to a subject in an amountsufficient to block TIGIT in the subject.

In some embodiments, a method of treating an infection or infectiousdisease in a human subject comprises administering to a subject who hasan infectious disease an effective amount of the isolated antigenbinding molecule or isolated antibody herein.

In some embodiments, a method for increasing an effectiveness of avaccine comprises administering a vaccine to a subject, andadministering any one or more of the isolated antigen binding moleculesor antibodies provided herein to the subject in an amount sufficient toserve as an adjuvant for the vaccine.

In some embodiments, a method for treating an infection comprisesidentifying a subject that has a viral infection, a bacterial infection,parasitic infection, and/or a fungal infection, and administering anyone or more of the antigen binding molecules or isolated antibodiesprovided herein to the subject in an amount and for a durationsufficient to treat the viral infection, the bacterial infection, theparasitic infection, and/or the fungal infection.

In some embodiments, a method for preventing and/or inhibiting TIGITbinding to MHC class II to enhance antigen-specific T-cell activation orstimulating T-cell production of interleukin-2 in a subject comprisesadministering any one or more of the antigen binding molecules providedherein to a subject in an amount sufficient for preventing and/orinhibiting TIGIT binding to MHC class II in the subject.

In some embodiments, a method of preventing, treating and/or lesseningthe severity of a disease in a subject comprises modulating the activityof TIGIT in the subject by administering an effective amount of any oneor more of the isolated antigen binding molecules or isolated antibodyprovided herein, wherein the disease is selected from the groupconsisting of: systemic lupus erythematosus, rheumatoid arthritis,juvenile chronic arthritis, spondyloarthropathies, systemic sclerosis(scleroderma), idiopathic inflammatory myopathies (dermatomyositis,polymyositis), Sjogren's syndrome, systemic vasculitis, sarcoidosis,autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnalhemoglobinuria), autoimmune thrombocytopenia (idiopathicthrombocytopenic purpura, immune-mediated thrombocytopenia), thyroiditis(Grave's disease, Hashimoto's thyroiditis, juvenile lymphocyticthyroiditis, atrophic thyroiditis), diabetes mellitus, immune-mediatedrenal disease (glomerulonephritis, tubulointerstitial nephritis),demyelinating diseases of the central and peripheral nervous systemssuch as multiple sclerosis, idiopathic demyelinating polyneuropathy orGuillain-Barre syndrome, and chronic inflammatory demyelinatingpolyneuropathy, hepatobiliary diseases such as infectious hepatitis(hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmunechronic active hepatitis, primary biliary cirrhosis, granulomatoushepatitis, and sclerosing cholangitis, inflammatory bowel disorder (IBD)(ulcerative colitis: Crohn's disease), gluten-sensitive enteropathy, andWhipple's disease, autoimmune or immune-mediated skin diseases includingbullous skin diseases, erythema multiforme and contact dermatitis,psoriasis, allergic diseases such as asthma, allergic rhinitis, atopicdermatitis, food hypersensitivity and urticaria, immunologic diseases ofthe lung such as eosinophilic pneumonias, idiopathic pulmonary fibrosisand hypersensitivity pneumonitis, transplantation associated diseasesincluding graft rejection and graft-versus-host-disease. Infectiousdiseases including viral diseases such as AIDS (HIV infection),hepatitis A, B, C, D, and E, herpes, etc., bacterial infections, fungalinfections, protozoal infections and parasitic infections also may haveimmune and/or inflammatory components and/or etiology.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises at least one of: (a) (i) a heavy chain variableregion comprising the heavy chain of clone Ab117 (SEQ ID NO: 62) and(ii) a light chain variable region comprising the light chain of cloneAb117 (SEQ ID NO: 159); (b) (i) a heavy chain variable region comprisingthe heavy chain of clone Ab53 (SEQ ID NO: 199) and (ii) a light chainvariable region comprising the light chain of clone Ab53 (SEQ ID NO:214); (c) (i) a heavy chain variable region comprising the heavy chainof clone Ab40 (SEQ ID NO: 200) and (ii) a light chain variable regioncomprising the light chain of clone Ab40 (SEQ ID NO: 215); (d) (i) aheavy chain variable region comprising the heavy chain of clone Ab48(SEQ ID NO: 203) and (ii) a light chain variable region comprising thelight chain of clone Ab48 (SEQ ID NO: 218); (e) (i) a heavy chainvariable region comprising the heavy chain of clone Ab1 (SEQ ID NO: 299)and (ii) a light chain variable region comprising the light chain ofclone Ab1 (SEQ ID NO: 385); or (f) (i) a heavy chain variable regioncomprising the heavy chain of clone Ab143 (SEQ ID NO: 279) and (ii) alight chain variable region comprising the light chain of clone Ab143(SEQ ID NO: 365).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an alignment of various TIGIT sequences.

FIGS. 2A-2R depict embodiments of various anti-TIGIT antigen bindingmolecule sequences.

FIGS. 3A-3L depict embodiments of various anti-TIGIT antigen bindingmolecule sequences.

FIG. 4 depicts embodiments of various TIGIT sequences.

FIG. 5 shows embodiments of sequences of heavy chain CDRs of antigenbinding molecules.

DETAILED DESCRIPTION

Provided herein are antigen binding molecules that bind to the TIGITprotein, preferably, the human TIGIT human protein. FIG. 1 depicts asequence alignment of various forms of TIGIT, including the human TIGIT.Some embodiments of the antigen binding molecules are applicable fordiagnostic purposes. In some embodiments, the antigen binding moleculesare antibodies or antigen binding fragments thereof. In someembodiments, the antigen binding molecules are agonists, and therebyactivate or increase TIGIT mediated signaling. In some embodiments, theantigen binding molecules are antagonists, and thereby inhibit ordecrease TIGIT mediated signaling. The following description provides aninitial outline of abbreviations and definitions, followed by a set ofpreferred embodiments and examples.

Abbreviations

Throughout the detailed description and examples the followingabbreviations will be used:

ADCC: Antibody-dependent cellular cytotoxicity CDC: Complement-dependentcytotoxicity CDR: Complementarity determining region in theimmunoglobulin variable regions CHO: Chinese hamster ovary FR: Antibodyframework region: the immunoglobulin variable regions excluding the CDRregions. IC50: concentration resulting in 50% inhibition IgG:Immunoglobulin G mAb or Mab or MAb: Monoclonal antibody V region: Thesegment of IgG chains which is variable in sequence between differentantibodies. It extends to Kabat residue 109 in the light chain and 113in the heavy chain. VH: Immunoglobulin heavy chain variable region VK:Immunoglobulin kappa light chain variable region

Definitions

So that the various embodiments may be more readily understood, certaintechnical and scientific terms are specifically defined below. Unlessspecifically defined elsewhere in this document, all other technical andscientific terms used herein have the meaning commonly understood by oneof ordinary skill in the art to which this invention belongs.

As used herein, including the appended claims, the singular forms ofwords such as “a,” “an,” and “the,” include their corresponding pluralreferences unless the context clearly dictates otherwise.

“Administration” as it applies to an animal, human, experimentalsubject, cell, tissue, organ, or biological fluid, refers to contact ofan exogenous pharmaceutical, therapeutic, diagnostic agent, orcomposition to the animal, human, subject, cell, tissue, organ, orbiological fluid. “Administration” also means in vitro and ex vivotreatments, e.g., of a cell, by a reagent, diagnostic, binding compound,or by another cell. Administration can be of the antibody directly tothe subject. Administration can be via a vector or other approach aswell (administering nucleic acid that encodes the antibody).

“Treat”, “treating”, or “treatment” means to administer a therapeuticagent, such as a composition containing any of the antibodies orantigen-binding fragments provided herein, internally or externally to asubject or patient having one or more disease symptoms, or beingsuspected of having a disease, for which the agent has therapeuticactivity. Typically, the agent is administered in an amount effective toalleviate one or more disease symptoms in the treated subject orpopulation, whether by inducing the regression of or inhibiting theprogression of such symptom(s) by any clinically measurable degree. Theamount of a therapeutic agent that is effective to alleviate anyparticular disease symptom may vary according to factors such as thedisease state, age, and weight of the patient, and the ability of thedrug to elicit a desired response in the subject. Whether a diseasesymptom has been alleviated can be assessed by any clinical measurementtypically used by physicians or other skilled healthcare providers toassess the severity or progression status of that symptom. “Treatment”refers to both therapeutic treatment and prophylactic or preventativemeasures, wherein the object is to prevent or slow down (lessen) thetargeted pathologic condition or disorder. Those in need of treatmentinclude those already with the disorder as well as those prone to havethe disorder or those in whom the disorder is to be prevented.

“Mammal” for purposes of treatment refers to any animal classified as amammal, including humans, domestic and farm animals, and zoo, sports, orpet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats,rabbits, etc. Preferably, the mammal is human.

Administration “in combination with” one or more further therapeuticagents includes simultaneous (concurrent) and consecutive administrationin any order.

“Carriers” as used herein include pharmaceutically acceptable carriers,excipients, or stabilizers which are nontoxic to the cell or mammalbeing exposed thereto at the dosages and concentrations employed. Oftenthe physiologically acceptable carrier is an aqueous pH bufferedsolution. Examples of physiologically acceptable carriers includebuffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid; low molecular weight (less thanabout 10 residues) polypeptide; proteins, such as serum albumin,gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides, andother carbohydrates including glucose, mannose, or dextrins; chelatingagents such as EDTA; sugar alcohols such as mannitol or sorbitol;salt-forming counterions such as sodium; and/or nonionic surfactantssuch as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

The term TIGIT includes human TIGIT, cynomolgus monkey TIGIT and rhesusTIGIT as well as fragments thereof such as the mature fragment thereoflacking the signal peptide. In some embodiments, the amino acid sequenceof human TIGIT comprises the amino acid sequence disclosed in amino acidresidues 25-244 of Genbank Accession Number NP 776160.2 (amino acidresidues 1-24 correspond to a leader peptide.) In some embodiments, theamino acid sequence of cynomolgus monkey, e.g., Macaca fascicularisTIGIT comprises the amino acid sequence in Genbank Accession no. XP005548157. The amino acid sequence of rhesus monkey TIGIT is identicalto the amino acid sequence of cynomolgus monkey TIGIT. (Amino acidresidues 1-24 correspond to a leader peptide.) Examples of TIGITsequences are shown in FIG. 1 and FIG. 4. Unless specified otherwise,the term human TIGIT will denote the first sequence in FIG. 4 (with orwithout a leader peptide).

As used herein, the term “antigen binding molecule” includes bothantibodies and antigen binding fragments thereof. An antigen bindingmolecule that binds to TIGIT refers to an antibody or antigen-bindingfragment thereof that “specifically” binds to TIGIT. An antigen bindingmolecule that “specifically” binds to human TIGIT is an antigen bindingmolecule that binds to human TIGIT with a K_(D) of about 1 microM or ahigher affinity (e.g., 1 micromolar, 0.1 micromolar, 0.01 micromolar, 1nM-2 pM, 1 nM, 100 pM, 10 pM or 2 pM), but does not bind to otherproteins lacking this (or a part thereof) sequence. For example, anantigen binding molecule that “specifically binds” human TIGIT does notbind to human CD226 and human CD 155. In some embodiments, the antigenbinding molecule that specifically binds to TIGIT can bind to a fragmentof a TIGIT protein, as long as it also binds to the native form ofTIGIT. Where desired, a full length antibody can be designated as an“intact” antibody (as opposed to an antigen binding fragment of theintact antibody).

As used herein “cross-reactivity” refers to the ability of an antigenbinding molecule to react with a homologous protein from other species.Whether an antigen binding molecule specifically binds to human TIGITcan be determined using any assay known in the art. Examples of assaysknown in the art to determining binding affinity include surface plasmonresonance (e.g., BIACORE) or a similar technique (e.g. KinExa or OCTET).

The term “antibody” is used in the broadest sense and specificallycovers, for example, single anti-TIGIT monoclonal antibodies orantibodies that specifically bind to any of the other polypeptidesdescribed herein (including agonist, antagonist, and neutralizingantibodies), anti-TIGIT or antibody compositions with polyepitopicspecificity, single chain anti-TIGIT or other antibodies. The term“monoclonal antibody” as used herein refers to an antibody that is partof a substantially homogeneous collection of antibodies, i.e., theindividual antibodies comprising the population are identical except forpossible naturally-occurring mutations that may be present in minoramounts.

Some embodiments provided herein include non-human parental (e.g. mouseand rodent) anti-TIGIT antibodies and antigen-binding fragments thereofand methods of use thereof. These antibodies may be modified for anintended use, such as humanization of an antibody for use as a humantherapeutic antibody or fragment.

Some embodiments provided herein include anti-TIGIT antigen-bindingfragments and methods of use thereof. Examples of antigen-bindingfragments include, but are not limited to, Fab, Fab′, F(ab′)₂, and Fvfragments; diabodies; linear antibodies; single-chain antibodymolecules, e.g., sc-Fv; nanobodies and multispecific antibodies formedfrom antibody fragments.

Some embodiments provided herein include anti-TIGIT Fab fragments andmethods of use thereof. A “Fab fragment” is comprised of one light chainand the C_(H)1 and variable regions of one heavy chain. The heavy chainof a Fab molecule cannot form a disulfide bond with another heavy chainmolecule. An “Fab fragment” can be the product of papain cleavage of anantibody.

Some embodiments provided herein include anti-TIGIT antibodies andantigen-binding fragments thereof which comprise an Fc region andmethods of use thereof. An “Fc” region contains two heavy chainfragments comprising the C_(H)1 and C_(H)2 domains of an antibody. Thetwo heavy chain fragments are held together by two or more disulfidebonds and by hydrophobic interactions of the C_(H)3 domains.

Some embodiments provided herein include anti-TIGIT Fab′ fragments andmethods of use thereof. A “Fab′ fragment” contains one light chain and aportion or fragment of one heavy chain that contains the VH domain andthe C_(H)1 domain and also the region between the C_(H)1 and C_(H)2domains, such that an interchain disulfide bond can be formed betweenthe two heavy chains of two Fab′ fragments to form a F(ab′)2molecule.Also contemplated are anti-TIGIT F(ab′)2fragments and methods of usethereof. A “F(ab′)2fragment” contains two light chains and two heavychains containing a portion of the constant region between the C_(H)1and C_(H)2 domains, such that an interchain disulfide bond is formedbetween the two heavy chains. A F(ab′)2fragment thus is composed of twoFab′ fragments that are held together by a disulfide bond between thetwo heavy chains. An “F(ab′)2fragment” can be the product of pepsincleavage of an antibody.

Some embodiments provided herein include anti-TIGIT Fv fragments andmethods of use thereof. The “Fv region” comprises the variable regionsfrom both the heavy and light chains, but lacks the constant regions.

Some embodiments provided herein include anti-TIGIT scFv fragments andmethods of use thereof. The term “single-chain Fv” or “scFv” antibodyrefers to antibody fragments comprising the VH and VL domains of anantibody, wherein these domains are present in a single polypeptidechain. Generally, the Fv polypeptide further comprises a polypeptidelinker between the VH and VL domains which enables the scFv to form thedesired structure for antigen-binding. For a review of scFv, seePluckthun (1994) THE PHARMACOLOGY OF MONOCLONAL ANTIBODIES, vol. 113,Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315. Seealso, International Patent Application Publication No. WO 88/01649 andU.S. Pat. Nos. 4,946,778 and 5,260,203.

Some embodiments provided herein include a domain antibody. A “domainantibody” is an immunologically functional immunoglobulin fragmentcontaining only the variable region of a heavy chain or the variableregion of a light chain. In some instances, two or more V_(H) regionsare covalently joined with a peptide linker to create a bivalent domainantibody. The two V_(H) regions of a bivalent domain antibody may targetthe same or different antigens. In some embodiments, surrobodyarrangements can also be used with one or more of the CDRs and/orvariable chain regions provided herein. Surrobodies include an antibodyheavy chain paired with two surrogate light chain components. See, e.g.,Xu et al “Combinatorial surrobody libraries” PNAS; 105, 10756-10761,Jul. 29, 2008, and WO2013109994, US20150011736. In some embodiments, thesurrogate light chain can include a VpreB section and a lambda5 section.

Some embodiments provided herein include a bivalent antibody. A“bivalent antibody” comprises two antigen-binding sites. In someembodiments, the two binding sites have the same antigen specificities.However, bivalent antibodies may be bispecific. Some embodimentsprovided herein include bispecific antibodies.

Some embodiments provided herein include anti-TIGIT camelized singledomain antibodies and methods of use thereof. In certain embodiments,antibodies herein also include camelized single domain antibodies. See,e.g., Muyldermans et al. (2001) Trends Biochem. Sci. 26:230; Reichmannet al. (1999) J. Immunol. Methods 231:25; WO 94/04678; WO 94/25591; U.S.Pat. No. 6,005,079). In some embodiments, single domain antibodiescomprising two VH domains with modifications such that single domainantibodies are formed are provided.

Some embodiments provided herein include anti-TIGIT diabodies andmethods of use thereof. As used herein, the term “diabodies” refers tosmall antibody fragments with two antigen-binding sites, which fragmentscomprise a heavy chain variable domain (V_(H)) connected to a lightchain variable domain (V_(L)) in the same polypeptide chain (V_(H)-V_(L)or V_(L)-V_(H)). By using a linker that is too short to allow pairingbetween the two domains on the same chain, the domains are forced topair with the complementary domains of another chain and create twoantigen-binding sites. Diabodies are described more fully in, e.g., EP404,097; WO 93/11161; and Holliger et al. (1993) Proc. Natl. Acad. Sci.USA 90: 6444-6448. For a review of engineered antibody variantsgenerally see Holliger and Hudson (2005) Nat. Biotechnol. 23: 1126-1136.

Typically, an antigen binding molecule that is modified in some wayretains at least 10% of its binding activity (when compared to theparental antibody) when that activity is expressed on a molar basis.Preferably, an antigen binding molecule retains at least 20%, 50%, 70%,80%, 90%, 95% or 100% or more of the TIGIT binding affinity as theparental antibody. It is also intended that an antigen binding moleculecan include conservative or non-conservative amino acid substitutions(referred to as “conservative variants” or “function conserved variants”of the antigen binding molecule) that do not substantially alter itsbiologic activity.

Some embodiments provided herein include isolated anti-TIGIT antigenbinding molecules and methods of use thereof. “Isolated” antigen bindingmolecules (e.g., antibodies or antigen-binding fragments thereof) are atleast partially free of other biological molecules from the cells orcell cultures in which they are produced. Such biological moleculesinclude nucleic acids, proteins, lipids, carbohydrates, or othermaterial such as cellular debris and growth medium. An isolated antigenbinding molecule (e.g., antibody or antigen-binding fragment) mayfurther be at least partially free of expression system components suchas biological molecules from a host cell or of the growth mediumthereof. Generally, the term “isolated” is not intended to refer to acomplete absence of such biological molecules or to an absence of water,buffers, or salts or to components of a pharmaceutical formulation thatincludes the antibodies or fragments. In some embodiments, the antigenbinding molecule will be purified (1) to greater than 95% by weight ofantibody, and most preferably more than 99% by weight or (2) tohomogeneity by SDS-PAGE under reducing or nonreducing conditions using adye or stain such as, but not limited to, Coomassie blue or silverstain. Isolated antibody includes the antibody in situ withinrecombinant cells since at least one component of the antibody's naturalenvironment will not be present.

Some embodiments provided herein include anti-TIGIT chimeric antibodies(e.g., human constant domain/mouse variable domain) and methods of usethereof. As used herein, a “chimeric antibody” is an antibody having thevariable domain from a first antibody and the constant domain from asecond antibody, where the first and second antibodies are fromdifferent species. (U.S. Pat. No. 4,816,567; and Morrison et al, (1984)Proc. Natl. Acad. Sci. USA 81: 6851-6855). Typically, the variabledomains are obtained from an antibody from an experimental animal (the“parental antibody”), such as a rodent, and the constant domainsequences are obtained from human antibodies, so that the resultingchimeric antibody will be less likely to elicit an adverse immuneresponse in a human subject than the parental (e.g., mouse) antibody.Some embodiments provided herein include anti-TIGIT human antibodies.

Some embodiments provided herein include anti-TIGIT humanized antibodiesand antigen-binding fragments thereof (e.g., rat or mouse antibodiesthat have been humanized) and methods of use thereof. As used herein,the term “humanized antibody” refers to forms of antibodies that containsequences from both human and non-human (e.g. mouse or rat) antibodies.In general, the humanized antibody will comprise substantially all of atleast one, and typically two, variable domains, in which all orsubstantially all of the hypervariable loops correspond to those of anon-human immunoglobulin, and all or substantially all of the framework(FR) regions are those of a human immunoglobulin sequence. The humanizedantibody may optionally comprise at least a portion of a humanimmunoglobulin constant region (Fc). These options also apply to antigenbinding molecules.

In general, the basic antibody structural unit comprises a tetramer.Each tetramer includes two identical pairs of polypeptide chains, eachpair having one “light” (about 25 kDa) and one “heavy” chain (about50-70 kDa). The amino-terminal portion of each chain includes a variableregion of about 100 to 110 or more amino acids primarily responsible forantigen recognition. The carboxy-terminal portion of the heavy chain maydefine a constant region primarily responsible for effector function.Typically, human light chains are classified as kappa and lambda lightchains. Furthermore, human heavy chains are typically classified as mu,delta, gamma, alpha, or epsilon, and define the antibody's isotype asIgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavychains, the variable and constant regions are joined by a “J” region ofabout 12 or more amino acids, with the heavy chain also including a “D”region of about 10 more amino acids. See generally, FundamentalImmunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).

The variable regions of each light/heavy chain pair form the antibodybinding site. Thus, in general, an intact antibody has two bindingsites. Except in bifunctional or bispecific antibodies, the two bindingsites are, in general, the same.

Typically, the variable domains of both the heavy and light chainscomprise three hypervariable regions, also called complementaritydetermining regions (CDRs), located within relatively conservedframework regions (FR). The CDRs are usually aligned by the frameworkregions, enabling binding to a specific epitope. In general, fromN-terminal to C-terminal, both light and heavy chains variable domainscomprise FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The assignment ofamino acids to each domain is, generally, in accordance with thedefinitions of Sequences of Proteins of Immunological Interest, Kabat,et al.; National Institutes of Health, Bethesda, Md.; 5thed.; NIH Publ.No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, et al,(1977) J. Biol. Chem. 252:6609-6616; Chothia, et al, (1987) JMol. Biol.196:901-917 or Chothia, et al., (1989) Nature 342:878-883.

CDRs (e.g., CDRL1, CDRL2 and CDRL3 in the light chain variable domainand CDRH1, CDRH2 and CDRH3 in the heavy chain variable domain) can alsobe identified following Chothia and Lesk (1987) J. Mol. Biol. 196:901-917 (defining the CDR regions of an antibody by structure). As usedherein, the term “framework” or “FR” residues refers to those variabledomain residues other than the hypervariable region residues definedherein as CDR residues. Additional CDR delineations are in use and areencompassed herein. The Chothia approach refers to the location of thestructural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)).The AbM CDRs represent a compromise between the Kabat CDRs and Chothiastructural loops, and are used by Oxford Molecular's AbM antibodymodeling software. The “contact” CDRs are based on an analysis of theavailable complex crystal structures. The residues from each of theseCDRs are noted below.

TABLE 0.1 Loop Kabat AbM Chothia Contact L1 L24-L34 L24-L34 L26-L32L30-L36 L2 L50-L56 L50-L56 L50-L52 L46-L55 L3 L89-L97 L89-L97 L91-L96L89-L96 H1  H31-H35B  H26-H35B H26-H32  H30-H35B (Kabat Numbering) H1H31-H35 H26-H35 H26-H32 H30-H35 (Chothia Numbering) H2 H50-H65  H50-H58 H53-H55  H47-H58  H3 H95-H102 H95-H102 H96-H101 H93-H101

CDRs may comprise “extended CDRs” as follows: 24-36 or 24-34 (L1), 46-56or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 (H1), 50-65 or49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH. The variabledomain residues are numbered according to Kabat et al., supra, for eachof these definitions. As provided herein, any one or more of the aboveCDR definitions may be used to identify the CDRs of the anti-TIGITantibody, within any given heavy and/or light chain sequence. Thus, forany antibody chain sequence provided herein, all forms of the CDRcollection (all three within the chain) are contemplated. In someembodiments, the CDR sequences are those provided in FIGS. 3A-3L.

Depending on the amino acid sequence of the constant domain of theirheavy chains, immunoglobulins can be assigned to different classes.There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, andIgM, and several of these may be further divided into subclasses(isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. In someembodiments, the anti-TIGIT antibody can be any one of these isotypes.

“Isolated nucleic acid molecule” or “isolated polynucleotide” means aDNA or RNA of genomic, mRNA, cDNA, or synthetic origin or somecombination thereof which is not associated with all or a portion of apolynucleotide in which the isolated polynucleotide is found in nature,or is linked to a polynucleotide to which it is not linked in nature.For purposes of this disclosure, it should be understood that “a nucleicacid molecule comprising” a particular nucleotide sequence does notencompass intact chromosomes. Isolated nucleic acid molecules“comprising” specified nucleic acid sequences may include, in additionto the specified sequences, coding sequences for up to ten or even up totwenty or more other proteins or portions or fragments thereof, or mayinclude operably linked regulatory sequences that control expression ofthe coding region of the recited nucleic acid sequences, and/or mayinclude vector sequences.

The phrase “control sequences” refers to DNA sequences necessary for theexpression of an operably linked coding sequence in a particular hostorganism. The control sequences that are suitable for prokaryotes, forexample, include a promoter, optionally an operator sequence, and aribosome binding site. Eukaryotic cells are known to use promoters,polyadenylation signals, and enhancers.

A nucleic acid or polynucleotide is “operably linked” when it is placedinto a functional relationship with another nucleic acid sequence. Forexample, DNA for a presequence or secretory leader is operably linked toDNA for a polypeptide if it is expressed as a preprotein thatparticipates in the secretion of the polypeptide; a promoter or enhanceris operably linked to a coding sequence if it affects the transcriptionof the sequence; or a ribosome binding site is operably linked to acoding sequence if it is positioned so as to facilitate translation.Generally, but not always, “operably linked” means that the DNAsequences being linked are contiguous, and, in the case of a secretoryleader, contiguous and in reading phase. However, enhancers do not haveto be contiguous. Linking is accomplished by ligation at convenientrestriction sites. If such sites do not exist, the syntheticoligonucleotide adaptors or linkers are used in accordance withconventional practice.

As used herein, the expressions “cell,” “cell line,” and “cell culture”are used interchangeably and all such designations include progeny.Thus, the words “transformants” and “transformed cells” include theprimary subject cell and cultures derived therefrom without regard forthe number of transfers. It is also understood that not all progeny willhave precisely identical DNA content, due to deliberate or inadvertentmutations. Mutant progeny that have the same function or biologicalactivity as screened for in the originally transformed cell areincluded. Where distinct designations are intended, it will be clearfrom the context.

As used herein, “germline sequence” refers to a sequence of unrearrangedimmunoglobulin DNA sequences. Any suitable source of unrearrangedimmunoglobulin sequences may be used. Human germline sequences may beobtained, for example, from JOINSOLVER germline databases on the websitefor the National Institute of Arthritis and Musculoskeletal and SkinDiseases of the United States National Institutes of Health. Mousegermline sequences may be obtained, for example, as described inGiudicelli et al. (2005) Nucleic Acids Res. 33:D256-D261.

“Stringent conditions” or “high stringency conditions”, as definedherein, may be identified by those that: (1) employ low ionic strengthand high temperature for washing, for example 0.015 M sodiumchloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.;(2) employ during hybridization a denaturing agent, such as formamide,for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1%Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; or (3)employ 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mMsodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5× Denhardt'ssolution, sonicated salmon sperm DNA (50 microgram/ml), 0.1% SDS, and10% dextran sulfate at 42° C., with washes at 42° C. in 0.2×SSC (sodiumchloride/sodium citrate) and 50% formamide at 55° C., followed by ahigh-stringency wash consisting of 0.1×SSC containing EDTA at 55° C.

“Moderately stringent conditions” may be identified as described bySambrook et al., Molecular Cloning: A Laboratory Manual, New York: ColdSpring Harbor Press, 1989, and include the use of washing solution andhybridization conditions (e.g., temperature, ionic strength and % SDS)less stringent that those described above. An example of moderatelystringent conditions is overnight incubation at 37° C. in a solutioncomprising: 20% formamide, 5×SSC (150 mM NaCl, 15 mM trisodium citrate),50 mM sodium phosphate (pH 7.6), 5× Denhardt's solution, 10% dextransulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed bywashing the filters in 1×SSC at about 37-50° C. The skilled artisan willrecognize how to adjust the temperature, ionic strength, etc. asnecessary to accommodate factors such as probe length and the like.

The terms “TIGIT antagonist” and “antagonist of TIGIT activity” are usedinterchangeably and refer to a compound that interferes with the normalfunctioning of TIGIT, by inhibiting or blocking TIGIT polypeptideactivity. Examples of TIGIT antagonists include, but are not limited toantigen binding molecules that bind TIGIT, anti-TIGIT antibodies, andTIGIT-binding fragments of anti-TIGIT antibodies that specifically bindTIGIT such that the interaction between the TIGIT antagonist and TIGITresults in a reduction or cessation of TIGIT activity. It will beunderstood by one of ordinary skill in the art that in some instances, aTIGIT antagonist may antagonize one TIGIT activity without affectinganother TIGIT activity. For example, in some embodiments, a TIGITantagonist for use in certain of the methods herein is a TIGITantagonist that antagonizes TIGIT activity in response to one of PVRinteraction, PVRL3 interaction, or PVRL2 interaction, e.g., withoutaffecting or minimally affecting any of the other TIGIT interactions.PVR is also known as CD155 and PVRL2 is also known as PVRL2.

The terms “TIGIT agonist” and “agonist of TIGIT activity” are usedinterchangeably and refer to a compound that enhances or stimulates thenormal functioning of TIGIT by enhancing normal TIGIT activity(including, but not limited to, enhancing the stability of TIGIT orenhancing binding of TIGIT to one or more target ligands). For example,the TIGIT agonist can be selected from an antigen binding molecule,antibody, and an antigen-binding fragment thereof. It will be understoodby one of ordinary skill in the art that in some instances, a TIGITagonist may agonize one TIGIT activity without affecting another TIGITactivity. For example, a desirable TIGIT agonist for use in certain ofthe methods herein is a TIGIT agonist that agonizes TIGIT activity inresponse to, or in place of, one of PVR interaction, PVRL3 interaction,or PVRL2 interaction, e.g., without affecting or minimally affecting anyof the other TIGIT interactions.

The term “immune-related disease” means a disease in which a componentof the immune system of a mammal causes, mediates or otherwisecontributes to a morbidity in the mammal. Also included are diseases inwhich stimulation or intervention of the immune response has anameliorative effect on progression of the disease. Included within thisterm are immune-mediated inflammatory diseases, non-immune-mediatedinflammatory diseases, infectious diseases, immunodeficiency diseases,neoplasia, etc.

The term “T cell mediated disease” means an immune-related disease inwhich T cells directly or indirectly mediate or otherwise contribute toa morbidity in a mammal. The T cell mediated disease may be associatedwith cell mediated effects, lymphokine mediated effects, etc., and eveneffects associated with B cells if the B cells are stimulated, forexample, by the lymphokines secreted by T cells.

Examples of immune-related and inflammatory diseases, some of which areimmune or T cell mediated, which can be treated include systemic lupuserythematosus, rheumatoid arthritis, juvenile chronic arthritis,spondyloarthropathies, systemic sclerosis (scleroderma), idiopathicinflammatory myopathies (dermatomyositis, polymyositis), Sjogren'ssyndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia(immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmunethrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediatedthrombocytopenia), thyroiditis (Grave's disease, Hashimoto'sthyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis),diabetes mellitus, immune-mediated renal disease (glomerulonephritis,tubulointerstitial nephritis), demyelinating diseases of the central andperipheral nervous systems such as multiple sclerosis, idiopathicdemyelinating polyneuropathy or Guillain-Barre syndrome, and chronicinflammatory demyelinating polyneuropathy, hepatobiliary diseases suchas infectious hepatitis (hepatitis A, B, C, D, E and othernon-hepatotropic viruses), autoimmune chronic active hepatitis, primarybiliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis,inflammatory bowel disorder (IBD) (ulcerative colitis: Crohn's disease),gluten-sensitive enteropathy, and Whipple's disease, autoimmune orimmune-mediated skin diseases including bullous skin diseases, erythemamultiforme and contact dermatitis, psoriasis, allergic diseases such asasthma, allergic rhinitis, atopic dermatitis, food hypersensitivity andurticaria, immunologic diseases of the lung such as eosinophilicpneumonias, idiopathic pulmonary fibrosis and hypersensitivitypneumonitis, transplantation associated diseases including graftrejection and graft-versus-host-disease. Infectious diseases includingviral diseases such as AIDS (HIV infection), hepatitis A, B, C, D, andE, herpes, etc., bacterial infections, fungal infections, protozoalinfections and parasitic infections also may have immune and/orinflammatory components and/or etiology.

Several diseases of the skin are correlated with an aberrant immuneresponse and to autoimmunity. Diseases such as psoriasis are hallmarkedby skin blistering, skin flaking, edema and the presence ofautoantibodies that bind to skin proteins. TIGIT expression isupregulated in psoriatic skin vs. normal skin. Modulation of TIGITexpression and/or activity may be useful in treating the symptoms orunderlying causes of psoriasis.

The term inflammatory bowel disorder (“IBD”) describes a group ofchronic inflammatory disorders of unknown causes in which the intestine(bowel) becomes inflamed, often causing recurring cramps or diarrhea.The prevalence of IBD in the US is estimated to be about 200 per 100,000population. Patients with IBD can be divided into two major groups,those with ulcerative colitis (“UC”) and those with Crohn's disease(“CD”).

In patients with UC, there is an inflammatory reaction primarilyinvolving the colonic mucosa. The inflammation is typically uniform andcontinuous with no intervening areas of normal mucosa. Surface mucosalcells as well as crypt epithelium and submucosa are involved in aninflammatory reaction with neutrophil infiltration. Ultimately, thissituation typically progresses to epithelial damage with loss ofepithelial cells resulting in multiple ulcerations, fibrosis, dysplasiaand longitudinal retraction of the colon. CD differs from UC in that theinflammation extends through all layers of the intestinal wall andinvolves mesentery as well as lymph nodes. CD may affect any part of thealimentary canal from mouth to anus. The disease is often discontinuous,i.e., severely diseased segments of bowel are separated from apparentlydisease-free areas. In CD, the bowel wall also thickens which can leadto obstructions. In addition, fistulas and fissures are not uncommon.

Clinically, IBD is characterized by diverse manifestations oftenresulting in a chronic, unpredictable course. Bloody diarrhea andabdominal pain are often accompanied by fever and weight loss. Anemia isnot uncommon, as is severe fatigue. Joint manifestations ranging fromarthralgia to acute arthritis as well as abnormalities in liver functionare commonly associated with IBD. Patients with IBD also have anincreased risk of colon carcinomas compared to the general population.During acute “attacks” of IBD, work and other normal activity areusually impossible, and often a patient is hospitalized.

Although the cause of IBD remains unknown, several factors, such asgenetic, infectious and immunologic susceptibility, have beenimplicated. IBD is much more common in Caucasians, especially those ofJewish descent. The chronic inflammatory nature of the condition hasprompted an intense search for a possible infectious cause. Althoughagents have been found which stimulate acute inflammation, none has beenfound to cause the chronic inflammation associated with IBD. Thehypothesis that IBD is an autoimmune disease is supported by thepreviously mentioned extraintestinal manifestation of IBD as jointarthritis, and the known positive response to IBD by treatment withtherapeutic agents such as adrenal glucocorticoids, cyclosporine andazathioprine, which are known to suppress immune response. In addition,the GI tract, more than any other organ of the body, is continuouslyexposed to potential antigenic substances such as proteins from food,bacterial byproducts (LPS), etc.

Further, the risk of colon cancer is highly elevated in patients withsevere ulcerative colitis, particularly if the disease has existed forseveral years. About 20-25% of patients with IBD eventually requiresurgery for removal of the colon because of massive bleeding, chronicdebilitating illness, perforation of the colon, or risk of cancer.Surgery is also sometimes performed when other forms of medicaltreatment fail or when the side effects of steroids or other medicationsthreaten the patient's health. As surgery is invasive and drasticallylife altering, it is not a highly desirable treatment regimen, and istypically the treatment of last resort. In order to better understandthis disease and possibly treat it, experiments determined that TIGITwas upregulated both in CD and UC when compared to normal tissue.Modulation of the expression and/or activity of TIGIT may prove usefulin the treatment of one or more forms of IBD.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune inflammatorydisease that mainly involves the synovial membrane of multiple jointswith resultant injury to the articular cartilage. The pathogenesis is Tlymphocyte dependent and is associated with the production of rheumatoidfactors, auto-antibodies directed against self IgG, with the resultantformation of immune complexes that attain high levels in joint fluid andblood. These complexes in the joint may induce the marked infiltrate oflymphocytes and monocytes into the synovium and subsequent markedsynovial changes; the joint space/fluid if infiltrated by similar cellswith the addition of numerous neutrophils. Tissues affected areprimarily the joints, often in symmetrical pattern. However,extra-articular disease also occurs in two major forms. One form is thedevelopment of extra-articular lesions with ongoing progressive jointdisease and typical lesions of pulmonary fibrosis, vasculitis, andcutaneous ulcers. The second form of extra-articular disease is the socalled Felty's syndrome which occurs late in the RA disease course,sometimes after joint disease has become quiescent, and involves thepresence of neutropenia, thrombocytopenia and splenomegaly. This can beaccompanied by vasculitis in multiple organs with formations ofinfarcts, skin ulcers and gangrene. Patients often also developrheumatoid nodules in the subcutis tissue overlying affected joints; thenodules late stage have necrotic centers surrounded by a mixedinflammatory cell infiltrate. Other manifestations which can occur in RAinclude: pericarditis, pleuritis, coronary arteritis, interstitialpneumonitis with pulmonary fibrosis, keratoconjunctivitis sicca, andrheumatoid nodules.

Juvenile chronic arthritis is a chronic idiopathic inflammatory diseasewhich begins often at less than 16 years of age. Its phenotype has somesimilarities to RA; some patients who are rheumatoid factor positive areclassified as juvenile rheumatoid arthritis. The disease issub-classified into three major categories: pauciarticular,polyarticular, and systemic. The arthritis can be severe and istypically destructive and leads to joint ankylosis and retarded growth.Other manifestations can include chronic anterior uveitis and systemicamyloidosis.

The term “effective amount” is a concentration or amount of apolypeptide and/or agonist/antagonist which results in achieving aparticular stated purpose. An “effective amount” of a polypeptide oragonist or antagonist thereof may be determined empirically.Furthermore, a “therapeutically effective amount” is a concentration oramount of a polypeptide and/or agonist/antagonist which is effective forachieving a stated therapeutic effect, which may be achieved in a singledose or multiple doses over time. This amount may also be determinedempirically.

The term “cytotoxic agent” as used herein refers to a substance thatinhibits or prevents the function of cells and/or causes destruction ofcells. The term is intended to include radioactive isotopes (e.g., I¹³¹,I¹²⁵, Y⁹⁰ and Re¹⁸⁶), chemotherapeutic agents, and toxins such asenzymatically active toxins of bacterial, fungal, plant or animalorigin, or fragments thereof.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer. Examples of chemotherapeutic agents includeadriamycin, doxorubicin, epirubicin, 5-fluorouracil, cytosinearabinoside (“Ara-C”), cyclophosphamide, thiotepa, busulfan, cytoxin,taxoids, e.g., paclitaxel (Taxol, Bristol-Myers Squibb Oncology,Princeton, N.J.), and doxetaxel (Taxotere, Rhone-Poulenc Rorer, Antony,France), toxotere, methotrexate, cisplatin, melphalan, vinblastine,bleomycin, etoposide, ifosfamide, mitomycin C, mitoxantrone,vincristine, vinorelbine, carboplatin, teniposide, daunomycin,caminomycin, aminopterin, dactinomycin, mitomycins, esperamicins (seeU.S. Pat. No. 4,675,187), melphalan and other related nitrogen mustards.Also included in this definition are hormonal agents that act toregulate or inhibit hormone action on tumors such as tamoxifen andonapristone.

As used herein, the term “inflammatory cells” designates cells thatenhance the inflammatory response such as mononuclear cells,eosinophils, macrophages, and polymorphonuclear neutrophils (PMN).

Exemplary Anti-TIGIT Antigen Binding Molecules

FIGS. 2A-2R and 3A-3L depict various sequences of anti-TIGIT antigenbinding molecules. In some embodiments, the anti-TIGIT antigen bindingmolecule (including an anti-TIGIT antibody or antigen binding fragmentthereof) results in immune cell activation. In some embodiments, theantigen binding molecule (including an anti-TIGIT antibody or antigenbinding fragment thereof) increase the activity of an immune cell. Theincrease of the activity of an immune cell can be detected using anymethod known in the art. In one embodiment, the increase in activity ofan immune cell can be detected by measuring the proliferation of theimmune cell. For example, an increase in activity of a T cell can bedetected by measuring the proliferation of the T cell or signaltransduction events such as tyrosine phosphorylation of immune receptorsor downstream kinases that transmit signals to transcriptionalregulators. In some embodiments, the increase in activity of an immunecell can be detected by measuring CTL or NK cell cytotoxic function onspecific target cells. In some embodiments, the increase in activity ofan immune cell can be detected by measuring t cell activation ex vivo ina sample derived from the subject. In some embodiments, the antigenbinding molecule (such as a full length antibody or fragment thereof)includes the paired heavy and light chain sequences. In someembodiments, the antigen binding molecule includes the 3 heavy chainCDRs and the three light chain CDRs noted in FIGS. 2A-3L.

An antagonist anti-TIGIT antigen binding molecule (e.g., an anti-TIGITantibody or antigen binding fragment thereof) antagonizes an activity ofhuman TIGIT such as by inhibiting TIGIT binding to cd155 and cd112, andinhibiting functional ITIM signal transduction by TIGIT upon binding tocd155 and cd112. Measurement of anti-TIGIT antagonist activity can beassessed by demonstrating blocking of t cell suppression following TCRactivation induced by TIGIT ligation with cognate ligands cd 155 andcd112. Hence, in some embodiments of increased responses, treating withantagonist anti-TIGIT antigen binding molecules (e.g., an anti-TIGITantibody or antigen binding fragment thereof) are able to rescue il-2responses to levels observed in t cells that are not repressed by cd155or cd112 induction of TIGIT. In a more preferred level of activation,responses, following treatment with an anti-TIGIT antagonist antigenbinding molecules (e.g., an anti-TIGIT antibody or antigen bindingfragment thereof) may increase responses to a level higher than t cellresponses not repressed by cd 155 or cd112.

In some embodiments, the anti-TIGIT antigen binding molecules (e.g., ananti-TIGIT antibody or antigen binding fragment thereof) are able toblock binding of human TIGIT to human CD 155 and human CD112. Theability to block binding of human TIGIT to human CD155 and human CD112can be determined using any method known in the art. In someembodiments, the ability of the antigen binding molecules (e.g., ananti-TIGIT antibody or antigen binding fragment thereof) to blockbinding of human TIGIT to human cd 155 and human CD112 is determinedusing an ELISA assay.

Also included are polypeptides, e.g., immunoglobulin polypeptides,comprising amino acid sequences that are at least about 75% identical,80% identical, more preferably at least about 90% identical and mostpreferably at least about 95% identical (e.g., 95%, 96%, 97%, 98%, 99%,100%) to the amino acid sequences of the antigen binding molecules(e.g., an anti-TIGIT antibody or antigen binding fragment thereof)provided herein (e.g., an antigen binding molecule that includes one ormore of the sequences in FIGS. 2A-3L) when the comparison is performedby a blast algorithm wherein the parameters of the algorithm areselected to give the largest match between the respective sequences overthe entire length of the respective reference sequences (e.g. Expectthreshold: 10; word size: 3; max matches in a query range: 0; blosum 62matrix; gap costs: existence 11, extension 1; conditional compositionalscore matrix adjustment).

Sequence identity refers to the degree to which the amino acids of twopolypeptides are the same at equivalent positions when the two sequencesare optimally aligned.

The following references relate to blast algorithms often used forsequence analysis: blast algorithms: Altschul et al. (2005) FEBS J.272(20): 5101-5109; Altschul, S. F., et al., (1990) J. Mol. Biol.215:403-410; Gish, W., et al., (1993) Nature Genet. 3:266-272; Madden,T. L., et al, (1996) Meth. Enzymol. 266: 131-141; Altschul, S. F., etal., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al, (1997)Genome Res. 7:649-656; Wootton, J. C., et al, (1993) Comput. Chem. 17:149-163; Hancock, J. M. et al., (1994) Comput. Appl. Biosci. 10:67-70;Alignment scoring systems: Dayhoff, M. O., et al, “A model ofevolutionary change in proteins.” in Atlas of Protein Sequence andStructure, (1978) vol. 5, suppl. 3. M. O. Dayhoff (ed.), pp. 345-352,Natl. Biomed. Res. Found., Wash., D.C.; Schwartz, R. M., et al.,“Matrices for detecting distant relationships.” in Atlas of ProteinSequence and Structure, (1978) vol. 5, suppl. 3.” M. O. Dayhoff (ed.),pp. 353-358, Natl. Biomed. Res. Found., Wash., D.C.; Altschul, S. F.,(1991) J. Mol. Biol. 219:555-565; States, D. J., et al, (1991) Methods3:66-70; Henikoff, S., et al, (1992) Proc. Natl. Acad. Sci. USA89:10915-10919; Altschul, S. F., et al., (1993) J. Mol. Evol.36:290-300; alignment statistics: Karlin, S., et al, (1990) Proc. Natl.Acad. Sci. USA 87:2264-2268; Karlin, S., et al, (1993) Proc. Natl. Acad.Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob.22:2022-2039; and Altschul, S. F. “Evaluating the statisticalsignificance of multiple distinct local alignments.” in Theoretical andComputational Methods in Genome Research (S. Suhai, ed.), (1997) pp.1-14, Plenum, N.Y.

Binding affinity by way of example, and not limitation, the antigenbinding molecules (e.g., an anti-TIGIT antibody or antigen bindingfragment thereof) disclosed herein may bind human TIGIT with a K_(D)value at least as good as about 1×10⁻⁹M (e.g., a K_(D) value of 1×10⁻⁹Mor lower numerically) as determined by surface plasmon resonance (e.g.,Biacore) or a similar technique (e.g. Kinexa or octet). In oneembodiment, the antigen binding molecules (e.g., an anti-TIGIT antibodyor antigen binding fragment thereof) disclosed herein may bind humanTIGIT with a K_(D) value at least as good as about 1×10⁻⁹M to about1×10⁻¹²M as determined by surface plasmon resonance (e.g., Biacore) or asimilar technique (e.g. Kinexa or octet). In some embodiments, theantigen binding molecules (e.g., an anti-TIGIT antibody or antigenbinding fragment thereof) disclosed herein may bind human TIGIT with aK_(D) value of at about 1×10⁻⁹M to about 1×10⁻¹²M as determined bysurface plasmon resonance (e.g., Biacore) or a similar technique (e.g.Kinexa or octet). In some embodiments, the antigen binding molecules(e.g., an anti-TIGIT antibody or antigen binding fragment thereof)disclosed herein may bind human TIGIT with a K_(D) value of at leastabout 50 pm (i.e, a K_(D) value of about 50 pm or lower) as determinedby Biacore or a similar technique. In one embodiment, the antigenbinding molecules (e.g., an anti-TIGIT antibody or antigen bindingfragment thereof) disclosed herein may bind human TIGIT with a K_(D)value of at least as good as about 10 pM (e.g., a KD numerical value ofabout 10 pm lower) as determined by Biacore or a similar technique. Inone embodiment, the antigen binding molecules (e.g., an anti-TIGITantibody or antigen binding fragment thereof) may bind to human TIGITwith a KD of about 50 pm to about 1 pm as determined by Biacore or asimilar technique.

The anti-TIGIT antigen binding molecules (e.g., an anti-TIGIT antibodyor antigen binding fragment thereof) disclosed herein (e.g., an antigenbinding molecule that includes one or more of the sequences in FIGS.2A-3L) may also be conjugated to a chemical moiety. The chemical moietymay be, inter alia, a polymer, a radionuclide or a cytotoxic factor. Insome embodiments, the chemical moiety is a polymer which increases thehalf-life of the antigen binding molecule (e.g., an anti-TIGIT antibodyor antigen binding fragment thereof) in the body of a subject. Suitablepolymers include, but are not limited to, hydrophilic polymers whichinclude but are not limited to polyethylene glycol (peg) (e.g., peg witha molecular weight of 2 kda, 5 kda, 10 kda, 12 kda, 20 kda, 30 kda or 40kda), dextran and monomethoxypolyethylene glycol (mpeg). Lee, et al.,(1999) (Bioconj. Chem. 10:973-981) discloses peg conjugated single-chainantibodies. Wen, et al., (2001) (Bioconj. Chem. 12:545-553) discloseconjugating antibodies with peg which is attached to a radiometalchelator (diethylenetriaminpentaacetic acid (dtp a)).

The antigen binding molecule (e.g., an anti-TIGIT antibody or antigenbinding fragment thereof) disclosed herein (e.g., an antigen bindingmolecule that includes one or more of the sequences in FIGS. 2A-3L) mayalso be conjugated with labels such as ⁹⁹Tc, ⁹⁰Yy, ¹¹¹In, ³²P, ¹⁴C,¹²⁵L, ³H, ¹³¹I, ¹¹C, ¹⁵O, ¹³N, ¹⁸F, ³⁵S, ⁵¹Cr, ⁵⁷To, ²²⁶Ra, ⁶⁰Co, ⁵⁹Fe,⁵⁷Se, ¹⁵²Eu, ⁶⁷Cu, ²¹⁷Ci, ²¹¹At, ²¹²Pb, ⁴⁷Sc, ¹⁰⁹Pd, ²³⁴Th, ⁴⁰K, ¹⁵⁷Gd,⁵⁵Mn, ⁵²Tr, and ⁵⁶Fe.

The antigen binding molecule (e.g., an anti-TIGIT antibody or antigenbinding fragment thereof) disclosed herein (e.g., an antigen bindingmolecule that includes one or more of the sequences in FIGS. 2A-3L) mayalso be pegylated, for example to increase its biological (e.g., serum)half-life. To pegylate, the antigen binding molecule (e.g., ananti-TIGIT antibody or antigen binding fragment thereof), typically isreacted with a reactive form of polyethylene glycol (peg), such as areactive ester or aldehyde derivative of peg, under conditions in whichone or more peg groups become attached to the antigen binding molecule.In particular embodiments, the pegylation is carried out via anacylation reaction or an alkylation reaction with a reactive pegmolecule (or an analogous reactive water-soluble polymer). As usedherein, the term “polyethylene glycol” is intended to encompass any ofthe forms of peg that have been used to derivatize other proteins, suchas mono (ci-cio) alkoxy- or aryloxy-polyethylene glycol or polyethyleneglycol-maleimide. In some embodiments, the antigen binding molecule tobe pegylated is an aglycosylated antibody or fragment. Methods forpegylating proteins are known in the art and can be applied to theantibodies. See, e.g., ep 0 154 316 and ep 0 401 384.

The antigen binding molecules (e.g., an anti-TIGIT antibody or antigenbinding fragment thereof) disclosed herein (e.g., an antigen bindingmolecule that includes one or more of the sequences in FIGS. 2A-3L) mayalso be conjugated with fluorescent or chemiluminescent labels,including fluorophores such as rare earth chelates, fluorescein and itsderivatives, rhodamine and its derivatives, isothiocyanate,phycoerythrin, phycocyanin, allophycocyanin, o-phthaladehyde,fluorescamine, ¹⁵²Eu, dansyl, umbelliferone, luciferin, luminal label,isoluminal label, an aromatic acridinium ester label, an imidazolelabel, an acridimium salt label, an oxalate ester label, an aequorinlabel, 2,3-dihydrophthalazinediones, biotin/avidin, spin labels andstable free radicals.

In some embodiments, an isolated antigen binding molecule that competesfor binding to human TIGIT with an antibody that comprises any one ormore of a CDR within any of FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J,2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J,3K, or 3L is provided. In some embodiments, the isolated antigen bindingmolecule comprises all 6 CDRs from a single clone in any one of FIG. 2A,2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 3A,3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L. In some embodiments, theisolated antigen binding molecule comprises at least 1, 2, 3, 4, or 5CDRs from a single clone in any one of FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G,2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q, 2R, 3A, 3B, 3C, 3D, 3E, 3F, 3G,3H, 3I, 3J, 3K, or 3L. In some embodiments, the isolated antigen bindingmolecule comprises a heavy and a light chain variable region from asingle clone identified in any one of FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G,2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R. In addition to the above,the CDR variants described within table 6.1 by position are alsoembodiments for a TIGIT antigen binding molecule.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT is provided. The isolated antigen binding moleculescomprises a) a heavy chain CDR1 comprising the amino acid sequence ofany one of the HCDR1s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J,3K, or 3L, b) a heavy chain CDR2 comprising the amino acid sequence ofany one of the HCDR2s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J,3K, or 3L, and c) a heavy chain CDR3 comprising the amino acid sequenceof any one of the HCDR3s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J,3K, or 3L. The HCDR1, HCDR2, and HCDR3 are from a same clone.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT is provided. The isolated antigen binding molecule comprisesa) a heavy chain CDR1 comprising the amino acid sequence of any of oneof the HCDR1s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L,b) a heavy chain CDR2 comprising the amino acid sequence of any one ofthe HCDR2s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, c)a heavy chain CDR3 comprising the amino acid sequence of any one of theHCDR3s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, d) alight chain CDR1 comprising the amino acid sequence of any one of theLCDR1s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, e) alight chain CDR2 comprising the amino acid sequence of any one of theLCDR2s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, and f)a light chain CDR3 comprising the amino acid sequence of any one of theLCDR3s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L. TheHCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are from a same clone.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT is provided. The isolated antigen binding molecule comprisesa heavy chain comprising the heavy chain amino acid variable sequence inany one of FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N,2O, 2P, 2Q or 2R.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT is provide. The isolated antigen binding molecule comprisesa light chain comprising the light chain amino acid variable sequence inany one of FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N,2O, 2P, 2Q or 2R.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT is provided. The isolated antigen binding molecule comprisesa heavy chain comprising the heavy chain amino acid variable sequence inany one of FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N,2O, 2P, 2Q or 2R and a light chain comprising the light chain amino acidvariable sequence in any one of FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I,2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT is provided. The isolated antigen binding molecule comprisesa heavy chain CDR1 comprising SSYX₄MX₆ (SEQ ID NO: 1600; FIG. 5) whereinX₄ is A, G, or S and X₆ is H, N, or S, and a heavy chain CDR2 comprisingWVY₃Y₄IY₆Y₇Y₈Y₉Y₁₀Y₁₁Y₁₂Y₁₃ (SEQ ID NO: 1601; FIG. 5) wherein Y₃ is S orA, Y₄ is G, N, S, Y, or A, Y₆ is S, K, or N, Y₇ is S, Y, or G, Y₈ is Nor S, Y₉ is G, S, A, or T, Y₁₀ is G or S, Y₁₁ is S, N, or T, Y₁₂ is T,K, S, or I, Y₁₃ is S, Y, or G, and a heavy chain CDR3 comprisingARZ₃PYZ₆Z₇WZ₉D (SEQ ID NO: 1602; FIG. 5), wherein Z₃ is V, A, G, or E,Z₆ is S, D, or G, Z₇ is V or Y, and Z₉ is I, A, M, or L. In someembodiments, the antigen binding molecule comprises 1, 2, 3, 4, 5, orall 6 of the above CDRs. In some embodiments, and one or more of thevariable positions in the CDRs can be replaced with a conservativesubstitution.

In some embodiments, an isolated binding molecule that binds to humanTIGIT is provided. The isolated antigen binding molecule comprises atleast one of: a) (i) a heavy chain variable region comprising the aminoacid sequence of SEQ ID NO: 23 and (ii) a light chain variable regioncomprising the amino acid sequence of SEQ ID NO: 120, b) (i) a heavychain variable region comprising the amino acid sequence of SEQ ID NO:29 and (ii) a light chain variable region comprising the amino acidsequence of SEQ ID NO: 126, c) (i) a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 45 and (ii) a lightchain variable region comprising the amino acid sequence of SEQ ID NO:142, d) (i) a heavy chain variable region comprising the amino acidsequence of SEQ ID NO: 46 and (ii) a light chain variable regioncomprising the amino acid sequence of SEQ ID NO: 143, e) (i) a heavychain variable region comprising the amino acid sequence of SEQ ID NO:58 and (ii) a light chain variable region comprising the amino acidsequence of SEQ ID NO: 155; f) (i) a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 63 and (ii) a lightchain variable region comprising the amino acid sequence of SEQ ID NO:160, g) (i) a heavy chain variable region comprising the amino acidsequence of SEQ ID NO: 67 and (ii) a light chain variable regioncomprising the amino acid sequence of SEQ ID NO:164, h) (i) a heavychain variable region comprising the amino acid sequence of SEQ ID NO:72 and (ii) a light chain variable region comprising the amino acidsequence of SEQ ID NO: 169, I) (i) a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 80 and (ii) a lightchain variable region comprising the amino acid sequence of SEQ ID NO:177, or j) (i) a heavy chain variable region that is at least 85%identical to any of the heavy chain variable regions in (a)-(i) and (ii)a light chain variable region that is at least 85% identical to any ofthe light chain variable regions in (a)-(i).

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT is provided. The isolated antigen binding molecule comprisesa heavy chain CDR3 of contiguous amino acids Z₁Z₂Z₃Z₄Z₅Z₆Z₇Z₈Z₉Z₁₀ (SEQID NO: 1599; FIG. 5) wherein Z₁ is A, Z₂ is R, Z₃ is E, Z₄ is P, Z₅ isY, Z₆ is D, G, or S, Z₇ is V, Y, or T, Z₈ is W, Z₉ is I, L, or M, andZ₁₀ is D. In some embodiments, Z₆ is D. In some embodiments, Z₆ is G. Insome embodiments, Z₆ is S. In some embodiments, Z₇ is V. In someembodiments, Z₇ is Y. In some embodiments, Z₇ is T. In some embodiments,Z₉ is I. In some embodiments, Z₉ is L. In some embodiments, Z₉ is M.

In some embodiments, an isolated antibody that comprises: a) a heavychain CDR1 comprising the amino acid sequence of any of one of theHCDR1s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, b) aheavy chain CDR2 comprising the amino acid sequence of any one of theHCDR2s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, c) aheavy chain CDR3 comprising the amino acid sequence of any one of theHCDR3s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, d) alight chain CDR1 comprising the amino acid sequence of any one of theLCDR1s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, e) alight chain CDR2 comprising the amino acid sequence of any one of theLCDR2s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, and f)(f) a light chain CDR3 comprising the amino acid sequence of any one ofthe LCDR3s in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L isprovided. The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are from asame clone.

In some embodiments, the isolated antibody comprises a heavy chaincomprising the heavy chain amino acid variable sequence in any one ofFIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Qor 2R, or a sequence at least 90% identical thereto.

In some embodiments, the isolated antibody comprises a light chaincomprising the light chain amino acid variable sequence in any one ofFIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Qor 2R, or a sequence at least 90% identical thereto.

In some embodiments, the isolated antibody comprises a heavy chaincomprising the heavy chain amino acid variable sequence in any one ofFIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Qor 2R, or a sequence at least 90% identical thereto, and a light chaincomprising the light chain amino acid variable sequence in any one ofFIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Qor 2R or a sequence at least 90% identical thereto.

In some embodiments, the isolated antigen binding molecule isolatedantibody binds to human TIGIT with a K_(D) of 1×10⁻⁷M or lower(numerically).

In some embodiments, the isolated antigen binding molecule or isolatedantibody has antagonist activity to human TIGIT.

In some embodiments, the antigen binding molecule is an antibody. Insome embodiments, the antibody is an intact human antibody. In someembodiments, the antibody is an antibody binding fragment. In someembodiments, the antibody is a chimeric or a humanized antibody. In someembodiments, the antibody binds to human TIGIT with a K_(D) of 100 nM orless (numerically).

In some embodiments, the isolated antigen binding molecule or isolatedantibody blocks binding of human TIGIT to human CD155 and human CD112.

In some embodiments, the isolated antigen binding molecule or antibodyis a bispecific antibody. In some embodiments, the bispecific antibodyfurther binds to PD-1.

In some embodiments, the isolated antigen binding molecule binds tohuman TIGIT and comprises at least one of: a) (i) a heavy chain variableregion comprising the heavy chain of clone Ab117 and (ii) a light chainvariable region comprising the light chain of clone Ab117, b) (i) aheavy chain variable region comprising the heavy chain of clone Ab53 and(ii) a light chain variable region comprising the light chain of cloneAb53, c) (i) a heavy chain variable region comprising the heavy chain ofclone Ab40 and (ii) a light chain variable region comprising the lightchain of clone Ab40, d) (i) a heavy chain variable region comprising theheavy chain of clone Ab48 and (ii) a light chain variable regioncomprising the light chain of clone Ab48, e) (i) a heavy chain variableregion comprising the heavy chain of clone Ab1 and (ii) a light chainvariable region comprising the light chain of clone Ab1, or f) (i) aheavy chain variable region comprising the heavy chain of clone Ab143and (ii) a light chain variable region comprising the light chain ofclone Ab143. In some embodiments, rather than the heavy and light chainvariable regions of the above antibodies, the 6 CDRs are present in theantigen binding molecules.

Methods of Therapy

Further provided are methods for treating subjects, including humansubjects, in need of treatment with the isolated antigen bindingmolecules (e.g., an anti-TIGIT antibody or antigen binding fragmentthereof) disclosed herein (e.g., an antigen binding molecule thatincludes one or more of the sequences in FIGS. 2A-3L). In someembodiments, the antigen binding molecule (such as a full lengthantibody or fragment thereof) includes the paired heavy and light chainsequences. In some embodiments, the antigen binding molecule includesthe 3 heavy chain CDRs and the three light chain CDRs noted in FIGS.2A-3L. In some embodiments, the subject suffers from an infection or aninfectious disease. In some embodiments, the subject suffers fromcancer. In some embodiments, the cancer is a solid tumor which isinfiltrated by tumor-infiltrating lymphocytes which express TIGIT. Insome embodiments, the cancer is, e.g., osteosarcoma, rhabdomyosarcoma,neuroblastoma, kidney cancer, leukemia, renal transitional cell cancer,bladder cancer, Wilm's cancer, ovarian cancer, pancreatic cancer, breastcancer, prostate cancer, bone cancer, lung cancer (e.g., non-small celllung cancer), gastric cancer, colorectal cancer, cervical cancer,synovial sarcoma, head and neck cancer, squamous cell carcinoma,multiple myeloma, renal cell cancer, retinoblastoma, hepatoblastoma,hepatocellular carcinoma, melanoma, rhabdoid tumor of the kidney,Ewing's sarcoma, chondrosarcoma, brain cancer, glioblastoma, meningioma,pituitary adenoma, vestibular schwannoma, a primitive neuroectodermaltumor, medulloblastoma, astrocytoma, anaplastic astrocytoma,oligodendroglioma, ependymoma, choroid plexus papilloma, polycythemiavera, thrombocythemia, idiopathic myelofibrosis, soft tissue sarcoma,thyroid cancer, endometrial cancer, carcinoid cancer or liver cancer,breast cancer or gastric cancer. In some embodiments, the cancer ismetastatic cancer, e.g., of the varieties described above. In someembodiments, a method for treating a subject using an anti-TIGITantibody or antigen-binding fragment thereof (e.g., an antigen bindingmolecule that includes one or more of the sequences in FIGS. 2A-3L) isprovided. The subject suffers from a viral infection. In someembodiments, the viral infection is infection with a virus selected fromthe group consisting of human immunodeficiency virus (HIV), hepatitisvirus (a, b, or c), herpes virus (e.g., VZV, HSV-I, HSV-6, HSV-II, andCMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses,echovirus, rhinovirus, coxsackie virus, coronavirus, respiratorysyncytial virus, mumps virus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus or arboviralencephalitis virus.

In some embodiments, methods for treating subjects using an anti-TIGITantigen binding molecule (e.g., an anti-TIGIT antibody or antigenbinding fragment thereof) are provided, wherein the subject suffers froma bacterial infection. In some embodiments, the bacterial infection isinfection with a bacteria selected from the group consisting ofchlamydia, rickettsial bacteria, mycobacteria, staphylococci,streptococci, pneumonococci, meningococci and gonococci, klebsiella,proteus, serratia, pseudomonas, legionella, coryneb acteriumdiphtheriae, salmonella, bacilli, vibrio cholerae, clostridium tetan,clostridium botulinum, bacillus anthricis, yersinia pestis,mycobacterium leprae, mycobacterium lepromatosis, and borriella. In someembodiments, methods for treating subjects using an anti-TIGIT antigenbinding molecule (e.g., an anti-TIGIT antibody or antigen bindingfragment thereof) are provided, wherein the subject suffers from afungal infection. In some embodiments, the fungal infection is infectionwith a fungus selected from the group consisting of candida (albicans,krusei, glabrata, tropicalis, etc.), cryptococcus neoformans,aspergillus (fumigatus, niger, etc.), genus Mucorales (mucor, absidia,rhizopus), sporothrix schenkii, blastomyces dermatitidis,paracoccidioides brasiliensis, coccidioides immitis and histoplasmacapsulatum.

In some embodiments, methods for treating subjects using an anti-TIGITantigen binding molecule (e.g., an anti-TIGIT antibody or antigenbinding fragment thereof) are provided, wherein the subject suffers froma parasitic infection. In some embodiments, the parasitic infection isan infection with a parasite selected from the group consisting ofentamoeba histolytica, balantidium coli, naegleria fowleri,acanthamoeba, giardia lambia, cryptosporidium, pneumocystis carinii,plasmodium vivax, babesia microti, trypanosoma brucei, trypanosomacruzi, leishmania donovani, toxoplasma gondii and nippostrongylusbrasiliensis.

In some embodiments, a method for preventing or inhibiting TIGIT bindingto MHC class ii, enhancing antigen-specific t-cell activation orstimulating t-cell production of interleukin-2 in a subject (e.g.,human), for example, is provided wherein the subject suffers from canceror infectious disease (e.g., as discussed herein) comprisingadministering an effective amount of anti-TIGIT antigen binding molecule(e.g., an antigen binding molecule that includes one or more of thesequences in FIGS. 2A-3L), optionally in association with a furtherchemotherapeutic agent. In some embodiments, any one or more ofanti-TIGIT antigen binding molecules can be co-administered with one ormore chemotherapeutics, such as any of: adriamycin, doxorubicin,epirubicin, 5-fluorouracil, cytosine arabinoside (“Ara-C”),cyclophosphamide, thiotepa, busulfan, cytoxin, taxoids, e.g., paclitaxel(Taxol, Bristol-Myers Squibb Oncology, Princeton, N.J.), and doxetaxel(Taxotere, Rhone-Poulenc Rorer, Antony, France), toxotere, methotrexate,cisplatin, melphalan, vinblastine, bleomycin, etoposide, ifosfamide,mitomycin C, mitoxantrone, vincristine, vinorelbine, carboplatin,teniposide, daunomycin, caminomycin, aminopterin, dactinomycin,mitomycins, esperamicins (see U.S. Pat. No. 4,675,187), melphalan, otherrelated nitrogen mustards, and hormonal agents that act to regulate orinhibit hormone action on tumors such as tamoxifen and onapristone. Insome embodiments, any one or more of the anti-TIGIT antigen bindingmolecules can be co-administered with other immuno-oncologic agents,including either or both of anti-PD-1 and anti-PDL-1 antibodies.

In some embodiments, the subject can be a mammal such as a human, dog,cat, horse, cow, mouse, rat, monkey (e.g., cynomolgus monkey, e.g.,Macaca fascicularis) or rabbit. In preferred embodiments, the subject isa human subject.

In some embodiments, the antigen binding molecule (e.g., an anti-TIGITantibody or antigen binding fragment thereof) disclosed herein (e.g., anantigen binding molecule that includes one or more of the sequences inFIGS. 2A-3L) can be used alone, or in association with other, furthertherapeutic agents and/or therapeutic procedures, for treating orpreventing any disease such as cancer, e.g., as discussed herein, in asubject in need of such treatment or prevention. Compositions, e.g.,pharmaceutical compositions comprising a pharmaceutically acceptablecarrier, comprising such antibodies and fragments in association withfurther therapeutic agents are also contemplated.

In some embodiments, a method of treating a TIGIT related disorder isprovided. The method can comprise a) Identifying a subject with a TIGITrelated disorder and b) administering an effective dose of an isolatedantigen binding molecule or antibody as provided herein to the subject.In some embodiments, the TIGIT related disorder is selected from thegroup consisting of at least one of: HIV, psoriasis, arthritis,inflammatory bowel disease, and cancer. In some embodiments, the canceris at least one of: a solid tumor which is infiltrated bytumor-infiltrating lymphocytes which express TIGIT, osteosarcoma,rhabdomyosarcoma, neuroblastoma, kidney cancer, leukemia, renaltransitional cell cancer, bladder cancer, Wilm's cancer, ovarian cancer,pancreatic cancer, breast cancer, prostate cancer, bone cancer, lungcancer, non-small cell lung cancer, gastric cancer, colon cancer,colorectal cancer, cervical cancer, synovial sarcoma, head and neckcancer, squamous cell carcinoma, multiple myeloma, renal cell cancer,retinoblastoma, hepatoblastoma, hepatocellular carcinoma, melanoma,rhabdoid tumor of the kidney, Ewing's sarcoma, chondrosarcoma, braincancer, glioblastoma, meningioma, pituitary adenoma, vestibularschwannoma, a primitive neuroectodermal tumor, medulloblastoma,astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma,choroid plexus papilloma, polycythemia vera, thrombocythemia, idiopathicmyelofibrosis, soft tissue sarcoma, thyroid cancer, endometrial cancer,carcinoid cancer or liver cancer, breast cancer, gastric cancer, ametastatic cancer of the varieties described above.

In some embodiments, a method of enhancing T-cell activation isprovided. The method comprises a) diagnosing an individual with lowT-cell counts and b) administering an effective dose of the isolatedantigen binding molecule or isolated antibody as provided herein. Insome embodiments, T-cell activation is of CD8+ T cells.

In some embodiments, a method of preventing, treating and/or lesseningthe severity of an immune-related disease relating to aberrant immunecell response in a subject is provided. The method comprises modulatingthe activity of TIGIT in the subject by administering an effectiveamount of any one or more of the isolated antigen binding molecules orantibodies provided herein.

In some embodiments, a method of increasing or stimulating an immuneresponse is provided. The method includes administering in vitro or invivo an antagonist of TIGIT activity, and/or by inhibiting intracellularsignaling mediated by TIGIT binding to PVR (aka CD155), wherein theantagonist of TIGIT activity is any one or more of the isolated antigenbinding molecules or isolated antibodies as provided herein.

In some embodiments, a method of increasing T cell activation isprovided. The method comprises administering any one or more of theisolated antigen binding molecules or isolated antibodies providedherein to a subject in an amount sufficient to block TIGIT in thesubject.

In some embodiments, a method of treating an infection or infectiousdisease in a human subject is provided. The method comprisesadministering to a subject who has an infectious disease an effectiveamount of the isolated antigen binding molecule or isolated antibody asprovided herein.

In some embodiments, a method for increasing an effectiveness of avaccine is provided. The method comprises administering a vaccine to asubject and administering any one or more of the isolated antigenbinding molecules or antibodies provided herein to the subject in anamount sufficient to serve as an adjuvant for the vaccine.

In some embodiments, a method for treating an infection is provided. Themethod comprises identifying a subject that has a viral infection, abacterial infection, parasitic infection, and/or a fungal infection, andadministering any one or more of the antigen binding molecules orisolated antibodies provided herein to the subject in an amount and fora duration sufficient to treat the viral infection, the bacterialinfection, the parasitic infection, and/or the fungal infection. In someembodiments, In some embodiments, the viral infection is an infectionwith a virus selected from the group consisting of at least one of:human immunodeficiency virus (HIV), hepatitis virus (A, B, or C), herpesvirus (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein Barr virus),adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus,coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus,rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus,HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus,rabies virus, JC virus and arboviral encephalitis virus. In someembodiments, the bacterial infection is infection with a bacteriaselected from the group consisting of at least one or: Chlamydia,rickettsial bacteria, mycobacteria, staphylococci, streptococci,pneumonococci, meningococci and gonococci, klebsiella, proteus,serratia, pseudomonas, Legionella, Coryneb acterium diphtheriae,Salmonella, bacilli, Vibrio cholerae, Clostridium tetan, Clostridiumbotulinum, Bacillus anthricis, Yersinia pestis, Mycobacterium leprae,Mycobacterium lepromatosis, and Borriella. In some embodiments, thefungal infection is infection with a fungus selected from the groupconsisting of at least one of: Candida (albicans, krusei, glabrata,tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus,niger, etc.), Genus Mucorales (mucor, absidia, rhizopus), Sporothrixschenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis,Coccidioides immitis, and Histoplasma capsulatum. In some embodiments,the parasitic infection is infection with a parasite selected from thegroup consisting of at least one of: Entamoeba histolytica, Balantidiumcoli, Naegleria fowleri, Acanthamoeba, Giardia lambia, Cryptosporidium,Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosomabrucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, andNippostrongylus brasiliensis.

In some embodiments, a method for preventing and/or inhibiting TIGITbinding to MHC class II to enhance antigen-specific T-cell activation orstimulating T-cell production of interleukin-2 in a subject is provided.The method comprises administering any one or more of the antigenbinding molecules to a subject in an amount sufficient for preventingand/or inhibiting TIGIT binding to MHC class II in the subject.

In some embodiments, a method of preventing, treating and/or lesseningthe severity of a disease in a subject is provided. The method comprisesmodulating the activity of TIGIT in the subject by administering aneffective amount of any one or more of the isolated antigen bindingmolecules or isolated antibodies provided herein. The disease isselected from the group consisting of: systemic lupus erythematosus,rheumatoid arthritis, juvenile chronic arthritis, spondyloarthropathies,systemic sclerosis (scleroderma), idiopathic inflammatory myopathies(dermatomyositis, polymyositis), Sjogren's syndrome, systemicvasculitis, sarcoidosis, autoimmune hemolytic anemia (immunepancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmunethrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediatedthrombocytopenia), thyroiditis (Grave's disease, Hashimoto'sthyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis),diabetes mellitus, immune-mediated renal disease (glomerulonephritis,tubulointerstitial nephritis), demyelinating diseases of the central andperipheral nervous systems such as multiple sclerosis, idiopathicdemyelinating polyneuropathy or Guillain-Barre syndrome, and chronicinflammatory demyelinating polyneuropathy, hepatobiliary diseases suchas infectious hepatitis (hepatitis A, B, C, D, E and othernon-hepatotropic viruses), autoimmune chronic active hepatitis, primarybiliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis,inflammatory bowel disorder (IBD) (ulcerative colitis: Crohn's disease),gluten-sensitive enteropathy, and Whipple's disease, autoimmune orimmune-mediated skin diseases including bullous skin diseases, erythemamultiforme and contact dermatitis, psoriasis, allergic diseases such asasthma, allergic rhinitis, atopic dermatitis, food hypersensitivity andurticaria, immunologic diseases of the lung such as eosinophilicpneumonias, idiopathic pulmonary fibrosis and hypersensitivitypneumonitis, transplantation associated diseases including graftrejection and graft-versus-host-disease. Infectious diseases includingviral diseases such as AIDS (HIV infection), hepatitis A, B, C, D, andE, herpes, etc., bacterial infections, fungal infections, protozoalinfections and parasitic infections also may have immune and/orinflammatory components and/or etiology.

Pharmaceutical Compositions

To prepare pharmaceutical or sterile compositions of the anti-TIGITantigen binding molecule (e.g., an anti-TIGIT antibody or antigenbinding fragment thereof that includes one or more of the sequences inFIGS. 2A-3L) is admixed with a pharmaceutically acceptable carrier orexcipient. See, e.g., Remington's Pharmaceutical Sciences and U.S.Pharmacopeia: National Formulary, Mack Publishing Company, Easton, Pa.(1984). Formulations of therapeutic and diagnostic agents may beprepared by mixing with acceptable carriers, excipients, or stabilizersin the form of, e.g., lyophilized powders, slurries, aqueous solutionsor suspensions (see, e.g., Hardman, et al. (2001) Goodman and Gilman'sThe Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.;Gennaro (2000) Remington: The Science and Practice of Pharmacy,Lippincott, Williams, and Wilkins, New York, N.Y.; Avis, et al. (eds.)(1993) Pharmaceutical Dosage Forms: Parenteral Medications, MarcelDekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms:Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990)Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weinerand Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc.,New York, N.Y.).

Toxicity and therapeutic efficacy of the antigen binding molecule (e.g.,an anti-TIGIT antibody or antigen binding fragment thereof),administered alone or in combination with another therapeutic agent, canbe determined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., for determining the LD50 (the dose lethal to50% of the population) and the ED50 (the dose therapeutically effectivein 50% of the population). The dose ratio between toxic and therapeuticeffects is the therapeutic index (LD50/ED50). The data obtained fromthese cell culture assays and animal studies can be used in formulatinga range of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with little or no toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administration.

In some embodiments, a further therapeutic agent that is administered toa subject in association with an anti-TIGIT antigen binding molecule inaccordance with the Physicians' Desk Reference 2003 (Thomson Healthcare;57th edition (Nov. 1, 2002)). The mode of administration can vary.Routes of administration include oral, rectal, transmucosal, intestinal,parenteral; intramuscular, subcutaneous, intradermal, intramedullary,intrathecal, direct intraventricular, intravenous, intraperitoneal,intranasal, intraocular, inhalation, insufflation, topical, cutaneous,transdermal, or intra-arterial.

In some embodiments, the anti-TIGIT antigen binding molecule (e.g., ananti-TIGIT antibody or antigen binding fragment thereof that includesone or more of the sequences in FIGS. 2A-3L) can be administered by aninvasive route such as by injection. In some embodiments, an anti-TIGITantigen binding molecule (e.g., an anti-TIGIT antibody or antigenbinding fragment thereof), or pharmaceutical composition thereof, isadministered intravenously, subcutaneously, intramuscularly,intraarterially, intratumorally, or by inhalation, aerosol delivery.Administration by non-invasive routes (e.g., orally; for example, in apill, capsule or tablet) is also an option.

In some embodiments, a composition is provided. The compositioncomprises an isolated antigen binding molecule (such as an antibody) asprovided herein in an amount that is pharmaceutically acceptable and apharmaceutically acceptable carrier.

Polynucleotides

Provided herein are polynucleotides encoding any of the polypeptides orimmunoglobulin chains of anti-TIGIT antigen binding molecule (e.g., ananti-TIGIT antibody or antigen binding fragment thereof). For example,various embodiments include the polynucleotides encoding the amino acidsdescribed in FIGS. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M,2N, 2O, 2P, 2Q, 2R, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, and 3L,as well as polynucleotides which hybridize thereto and, also, anypolypeptide encoded by such a hybridizing polynucleotide.

In general, the polynucleotides hybridize under low, moderate or highstringency conditions, and encode antigen binding molecules (e.g., ananti-TIGIT antibody or antigen binding fragment thereof) that maintainthe ability to bind to TIGIT (human, rhesus and/or cynomolgus monkey,e.g., Macaca fascicularis). A first polynucleotide molecule is“hybridizable” to a second polynucleotide molecule when a singlestranded form of the first polynucleotide molecule can anneal to thesecond polynucleotide molecule under the appropriate conditions oftemperature and solution ionic strength (see Sambrook, et al., supra).The conditions of temperature and ionic strength determine the“stringency” of the hybridization. Typical low stringency hybridizationconditions include 55° C., 5×SSC, 0.1% SDS and no formamide; or 30%formamide, 5×SSC, 0.5% SDS at 42° C. Typical moderate stringencyhybridization conditions are 40% formamide, with 5× or 6×SSC and 0.1%SDS at 42° C. High stringency hybridization conditions are 50%formamide, 5× or 6×SSC at 42° C. or, optionally, at a higher temperature(e.g., 57° C., 59° C., 60° C., 62° C., 63° C., 65° C. or 68° C.). Ingeneral, SSC is 0.15M NaCl and 0.015M Na-citrate. Hybridization requiresthat the two polynucleotide contain complementary sequences, although,depending on the stringency of the hybridization, mismatches betweenbases are possible. The appropriate stringency for hybridizingpolynucleotides depends on the length of the polynucleotides and thedegree of complementation, variables well known in the art. The greaterthe degree of similarity or homology between two nucleotide sequences,the higher the stringency under which the nucleic acids may hybridize.For hybrids of greater than 100 nucleotides in length, equations forcalculating the melting temperature have been derived (see Sambrook, etal., supra, 9.50-9.51). For hybridization with shorter polynucleotides,e.g., oligonucleotides, the position of mismatches becomes moreimportant, and the length of the oligonucleotide determines itsspecificity (see Sambrook, et al., supra, 11.7-11.8).

In some embodiments, an isolated polynucleotide, for example DNA,encoding the polypeptide chains of the isolated antigen binding molecule(e.g., an anti-TIGIT antibody or antigen binding fragment thereof) setforth herein is provided. In some embodiments, the isolatedpolynucleotide encodes an antigen binding molecule (e.g., an anti-TIGITantibody or antigen binding fragment thereof) comprising at least onemature immunoglobulin light chain variable (VL) domain accordingincluding the sequences provided herein and/or at least one matureimmunoglobulin heavy chain variable (VH) domain including the sequencesprovided herein. In some embodiments the isolated polynucleotide encodesboth a light chain and a heavy chain on a single polynucleotidemolecule, and in other embodiments the light and heavy chains areencoded on separate polynucleotide molecules. In another embodiment thepolynucleotides further encodes a signal sequence. In some embodiments,the polynucleotide encodes one or more of the CDR sequences provided inany one of FIGS. 2A-3L.

Further envisioned are vectors, e.g., expression vectors, such asplasmids, comprising the above isolated polynucleotides, wherein thepolynucleotide is operably linked to control sequences that arerecognized by a host cell when the host cell is transfected with thevector. Also provided are host cells comprising such a vector andmethods for producing the antigen binding molecule (e.g., an anti-TIGITantibody or antigen binding fragment thereof) or polypeptide disclosedherein comprising culturing a host cell harboring an expression vectoror a nucleic acid encoding the immunoglobulin chains of the antigenbinding molecule (e.g., an anti-TIGIT antibody or antigen bindingfragment thereof) in culture medium, and isolating the antigen orantigen-binding fragment thereof from the host cell or culture medium.

Methods of Making

In some embodiments, a method of making an isolated antigen bindingmolecule that binds to human TIGIT is provided. The method comprisesproviding a nucleic acid that encodes for the isolated antigen bindingmolecule or isolated antibody provided herein, and expressing a proteinencoded by the nucleic acid. In some embodiments, the isolated antigenbinding molecule is expressed in a CHO cell.

Hybridoma cells that produce parental (e.g., rat or mouse) monoclonalanti-TIGIT antigen binding molecule (e.g., an anti-TIGIT antibody orantigen binding fragment thereof) discussed herein may be produced bymethods which are known in the art. Such isolated hybridomas are alsocontemplated in regard to the sequences provided in FIGS. 2A-3L. Themethods include, but are not limited to, the hybridoma techniqueoriginally developed by Kohler, et al., (1975) (Nature 256:495-497), aswell as the trioma technique (Hering, et al., (1988) Biomed. Biochim.Acta. 47:211-216 and Hagiwara, et al., (1993) Hum. Antibod. Hybridomas4: 15), the human B-cell hybridoma technique (Kozbor, et al., (1983)Immunology Today 4:72 and Cote, et al., (1983) Proc. Natl. Acad. Sci.U.S.A 80:2026-2030), the EBV-hybridoma technique (Cole, et al., inMonoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96,1985), and electric field based electrofusion using a Cyto Pulse largechamber cull fusion electroporator (Cyto Pulse Sciences, Inc., GlenBurnie, Md.).

Preferably, mouse splenocytes are isolated and fused with PEG or byelectrofusion to a mouse myeloma cell line based upon standardprotocols. The resulting hybridomas may then be screened for theproduction of antigen-specific antibodies. For example, single cellsuspensions of splenic lymphocytes from immunized mice may by fused toone-sixth the number of P3X63-Ag8.653 nonsecreting mouse myeloma cells(ATCC, CRL 1580) with 50% PEG. Cells may be plated at approximately2×10<5>cells/mL in a flat bottom microtiter plate, followed by a twoweek incubation in selective medium containing 20% fetal Clone Serum,18% “653” conditioned media, 5% origen (IGEN), 4 mM L-glutamine, 1 mML-glutamine, 1 mM sodium pyruvate, 5 mM HEPES, 0.055 mM2-mercaptoethanol, 50 units/ml penicillin, 50 mg/ml streptomycin, 50mg/ml gentamycin and IX HAT (Sigma; the HAT is added 24 hours after thefusion). After two weeks, cells may be cultured in medium in which theHAT is replaced with HT. Individual wells may then be screened by ELISAfor anti-TIGIT monoclonal IgG antibodies. Once extensive hybridomagrowth occurs, medium can be observed usually after 10-14 days. Theantibody secreting hybridomas may be replated, screened again, and ifstill positive for human IgG, anti-TIGIT monoclonal antibodies, can besubcloned at least twice by limiting dilution. The stable subclones maythen be cultured in vitro to generate small amounts of antibody intissue culture medium for characterization.

Thus, methods for making an anti-TIGIT antigen binding molecules (e.g.,an anti-TIGIT antibody or antigen binding fragment thereof) arecontemplated and comprise culturing a hybridoma cell that expresses theantigen binding molecule under conditions favorable to such expressionand, optionally, isolating the antigen binding molecule from thehybridoma and/or the growth medium (e.g. cell culture medium).

The anti-TIGIT antigen binding molecules disclosed herein may also beproduced recombinantly (e.g., in an E. coli/YI expression system, amammalian cell expression system or a lower eukaryote expressionsystem). In some embodiments, nucleic acids encoding the antibodyimmunoglobulin molecules (e.g., VH or VL or the relevant CDRs) may beinserted into a pET-based plasmid and expressed in the E. coli/T7system. For example, methods for expressing an antigen binding moleculeor immunoglobulin chain thereof in a host cell (e.g., bacterial hostcell such as E. coli such as BL21 or BL21DE3) comprise expressing T7 RNApolymerase in the cell which also includes a polynucleotide encoding animmunoglobulin chain that is operably linked to a T7 promoter. Forexample, a bacterial host cell, such as a E. coli, includes apolynucleotide encoding the T7 RNA polymerase gene operably linked to alac promoter and expression of the polymerase and the chain is inducedby incubation of the host cell with IPTG(isopropyl-beta-D-thiogalactopyranoside).

There are several methods by which to produce recombinant antibodieswhich are known in the art. One example of a method for recombinantproduction of antibodies is disclosed in U.S. Pat. No. 4,816,567.

Transformation can be achieved by any known method for introducingpolynucleotides into a host cell. Methods for introduction ofheterologous polynucleotides into mammalian cells are well known in theart and include dextran-mediated transfection, calcium phosphateprecipitation, polybrene-mediated transfection, protoplast fusion,electroporation, encapsulation of the polynucleotide(s) in liposomes,biolistic injection and direct microinjection of the DNA into nuclei. Inaddition, nucleic acid molecules may be introduced into mammalian cellsby viral vectors. Methods of transforming cells are well known in theart. See, for example, U.S. Pat. Nos. 4,399,216; 4,912,040; 4,740,461and 4,959,455.

In some embodiments, recombinant methods for making an anti-TIGITantigen binding molecules, or an immunoglobulin chain thereof, compriseintroducing a polynucleotide encoding one or more immunoglobulin chainsof the antigen binding molecule (e.g., heavy and/or light immunoglobulinchain); culturing the host cell (e.g., CHO or Pichia or Pichia pastoris)under condition favorable to such expression and, optionally, isolatingthe antigen binding molecule or chain from the host cell and/or mediumin which the host cell is grown. Anti-TIGIT antigen binding moleculescan also be synthesized by any of the methods set forth in U.S. Pat. No.6,331,415.

Eukaryotic and prokaryotic host cells, including mammalian cells ashosts for expression of the antigen binding molecules (includingimmunoglobulin chains) disclosed herein are well known in the art andinclude many immortalized cell lines available from the American TypeCulture Collection (ATCC). These include, inter alia, Chinese hamsterovary (CHO) cells, NSO, SP2 cells, HeLa cells, baby hamster kidney (BHK)cells, monkey kidney cells (COS), human hepatocellular carcinoma cells(e.g., Hep G2), A549 cells, 3T3 cells, HEK-293 cells and a number ofother cell lines. Mammalian host cells include human, mouse, rat, dog,monkey, pig, goat, bovine, horse and hamster cells. Cell lines ofparticular preference are selected through determining which cell lineshave high expression levels. Other cell lines that may be used areinsect cell lines, such as Sf9 cells, amphibian cells, bacterial cells,plant cells and fungal cells. Fungal cells include yeast and filamentousfungus cells including, for example, Pichia pastoris, Pichia finlandica,Pichia trehalophila, Pichia koclamae, Pichia membranaefaciens, Pichiaminuta (Ogataea minuta, Pichia lindneri), Pichia opuntiae, Pichiathermotolerans, Pichia salictaria, Pichia guercuum, Pichia pijperi,Pichia stiptis, Pichia methanolica, Pichia sp., Saccharomycescerevisiae, Saccharomyces sp., Hansenula polymorpha, Kluyveromyces sp.,Kluyveromyces lactic, Candida albicans, Aspergillus nidulans,Aspergillus niger, Aspergillus oryzae, Trichoderma reesei, Chrysosporiumlucknowense, Fusarium sp., Fusarium gramineum, Fusarium venenatum,Physcomitrella patens and Neurospora crassa. Pichia sp., anySaccharomyces sp., Hansenula polymorpha, any Kluyveromyces sp., Candidaalbicans, any Aspergillus sp., Trichoderma reesei, Chrysosporiumlucknowense, any Fusarium sp., Yarrowia lipolytica, and Neurosporacrassa. When recombinant expression vectors encoding the heavy chain orantigen-binding portion or fragment thereof, the light chain and/orantigen-binding fragment thereof are introduced into mammalian hostcells, the antigen binding molecules are produced by culturing the hostcells for a period of time sufficient to allow for expression of theantigen binding molecule or chain in the host cells or secretion of theinto the culture medium in which the host cells are grown.

Antigen binding molecules and immunoglobulin chains can be recoveredfrom the culture medium using standard protein purification methods.Further, expression of antigen binding molecules (includingimmunoglobulin chains (or other moieties therefrom)) from productioncell lines can be enhanced using a number of known techniques. Forexample, the glutamine synthetase gene expression system (the GS system)is a common approach for enhancing expression under certain conditions.The GS system is discussed in whole or part in connection with EuropeanPatent Nos. 0 216 846, 0 256 055, and 0 323 997 and European PatentApplication No. 89303964.4. Thus, in some embodiments, the mammalianhost cells {e.g., CHO) lack a glutamine synthetase gene and are grown inthe absence of glutamine in the medium wherein, however, thepolynucleotide encoding the immunoglobulin chain comprises a glutaminesynthetase gene which complements the lack of the gene in the host cell.

Methods for purifying an anti-TIGIT antigen binding molecule cancomprise introducing a sample comprising the antigen binding molecule toa purification medium (e.g., cation exchange medium, anion exchangemedium, hydrophobic exchange medium, affinity purification medium (e.g., protein-A, protein-G, protein-A/G, protein-L)) and either collectingpurified antigen binding molecule from the flow-through fraction of saidsample that does not bind to the medium; or, discarding the flow-throughfraction and eluting bound antigen binding molecule from the medium andcollecting the eluate. In some embodiments, the medium is in a column towhich the sample is applied. In some embodiments, the purificationmethod is conducted following recombinant expression of the antigenbinding molecule in a host cell, e.g. , wherein the host cell is firstlysed and, optionally, the lysate is purified of insoluble materialsprior to purification on a medium.

In general, glycoproteins produced in a particular cell line ortransgenic animal will have a glycosylation pattern that ischaracteristic for glycoproteins produced in the cell line or transgenicanimal. Therefore, the particular glycosylation pattern of an antibodywill depend on the particular cell line or transgenic animal used toproduce the antibody. In some embodiments, antibodies with aglycosylation pattern comprising only non-fucosylated N-glycans may beadvantageous, because these antibodies have been shown to typicallyexhibit more potent efficacy than their fucosylated counterparts both invitro and in vivo {See for example, Shinkawa et al., J. Biol. Chem. 278:3466-3473 (2003); U.S. Pat. Nos. 6,946,292 and 7,214,775). Theseantibodies with non-fucosylated N-glycans are not likely to beimmunogenic because their carbohydrate structures are a normal componentof the population that exists in human serum IgG.

Provided herein are polyclonal anti-TIGIT antibodies and antigen-bindingfragments thereof, e.g., a composition comprising a plurality ofanti-TIGIT antibodies and fragments, which include one or more of theanti-TIGIT antibodies or antigen-binding fragments thereof. A polyclonalantibody is an antibody which was produced among or in the presence ofone or more other, non-identical antibodies. In general, polyclonalantibodies are produced from collections of different B-lymphocytes,e.g., the B-lymphocyte of an animal treated with an immunogen ofinterest, which produces a population of different antibodies but whichare all directed to the immunogen. Usually, polyclonal antibodies areobtained directly from an immunized animal, e.g., spleen, serum orascites fluid.

The antigen binding molecules disclosed herein (e.g., an antigen bindingmolecule that includes one or more of the sequences in FIGS. 2A-3L) alsoinclude antigen binding molecules with modified (or blocked) Fc regionsto provide altered effector functions. See, e.g., U.S. Pat. No.5,624,821; WO2003/086310; WO2005/120571; WO2006/0057702. Suchmodifications can be used to enhance or suppress various reactions ofthe immune system, with possible beneficial effects in diagnosis andtherapy. Alterations of the Fc region include amino acid changes(substitutions, deletions and insertions), glycosylation ordeglycosylation, and adding multiple Fc regions. Changes to the Fc canalso alter the half-life of antigen binding molecules in therapeuticantigen binding molecules, enabling less frequent dosing and thusincreased convenience and decreased use of material. See Presta (2005)J. Allergy Clin. Immunol. 116:731 at 734-35.

In some embodiments, the Fc region of an anti-TIGIT antibody is modifiedto increase the ability of the antibody or antigen-binding fragment tomediate effector function and/or to increase their binding to theFcgamma receptors (FcyRs).

The term “Effector Function” as used herein is meant to refer to one ormore of Antibody Dependent Cell mediated Cytotoxic activity (ADCC),Complement-dependent cytotoxic activity (CDC) mediated responses,Fc-mediated phagocytosis or antibody dependent cellular phagocytosis(ADCP) and antibody recycling via the FcRn receptor.

The interaction between the constant region of an antigen bindingprotein and various Fc receptors (FcR) including FcgammaRI (CD64),FcgammaRII (CD32) and FcgammaRIII (CD 16) is believed to mediate theeffector functions, such as ADCC and CDC, of the antigen bindingprotein. The Fc receptor is also important for antibody cross-linking,which can be important for anti-tumor immunity.

Effector function can be measured in a number of ways including forexample via binding of the FcgammaRIII to Natural Killer cells or viaFcgammaRI to monocytes/macrophages to measure for ADCC effectorfunction. For example an antigen binding protein can be assessed forADCC effector function in a Natural Killer cell assay. Examples of suchassays can be found in Shields et al, 2001 J. Biol. Chem., Vol. 276, p6591-6604; Chappel et al, 1993 J. Biol. Chem., Vol 268, p 25124-25131;Lazar et al, 2006 PNAS, 103; 4005-4010.

The ADCC or CDC properties of antibodies, or their cross-linkingproperties, may be enhanced in a number of ways.

Human IgG1 constant regions containing specific mutations or alteredglycosylation on residue Asn297 have been shown to enhance binding to Fcreceptors. In some cases these mutations have also been shown to enhanceADCC and CDC (Lazar et al. PNAS 2006, 103; 4005-4010; Shields et al. JBiol Chem 2001, 276; 6591-6604; Nechansky et al. Mol Immunol, 2007, 44;1815-1817).

In some embodiments, such mutations are in one or more of positionsselected from 239, 332 and 330 (IgG1), or the equivalent positions inother IgG isotypes. Examples of suitable mutations are S239D and I332Eand A330L. In some embodiments, the antibody herein described is mutatedat positions 239 and 332, for example S239D and I332E or in a furtherembodiment it is mutated at three or more positions selected from 239and 332 and 330, for example S239D and I332E and A330L. (EU indexnumbering).

In some embodiments, there is provided an antibody comprising a heavychain constant region with an altered glycosylation profile such thatthe antigen binding protein has enhanced effector function. For example,wherein the antibody has enhanced ADCC or enhanced CDC or wherein it hasboth enhanced ADCC and CDC effector function. Examples of suitablemethodologies to produce antigen binding proteins with an alteredglycosylation profile are described in WO2003011878, WO2006014679 andEP1229125.

Kits

Further provided are kits comprising one or more components thatinclude, but are not limited to, an anti-TIGIT antigen binding molecule(e.g., an antibody or antigen binding fragment thereof, that includesone or more of the sequences in FIGS. 2A-3L) in association with one ormore additional components including, but not limited to apharmaceutically acceptable carrier and/or a therapeutic agent. Theantigen binding molecule and/or the therapeutic agent can be formulatedas a pure composition or in combination with a pharmaceuticallyacceptable carrier, in a pharmaceutical composition.

In some embodiments, a kit for determining the presence of human TIGITis provided. The kit can comprise an isolated antigen binding moleculeor isolated antibody as provided herein and a detectable marker.

In some embodiments, the kit includes an anti-TIGIT antigen bindingmolecule (e.g., an antibody or antigen binding fragment thereof, thatincludes one or more of the sequences in FIGS. 2A-3L) or apharmaceutical composition thereof in one container (e.g., in a sterileglass or plastic vial) and a pharmaceutical composition thereof and/or atherapeutic agent in another container (e.g., in a sterile glass orplastic vial).

In some embodiments, the kit comprises a combination, including ananti-TIGIT antigen binding molecule (e.g., an antibody or antigenbinding fragment thereof that includes one or more of the sequences inFIGS. 2A-3L) along with a pharmaceutically acceptable carrier,optionally in combination with one or more therapeutic agents formulatedtogether, optionally, in a pharmaceutical composition, in a single,common container.

If the kit includes a pharmaceutical composition for parenteraladministration to a subject, the kit can include a device for performingsuch administration. For example, the kit can include one or morehypodermic needles or other injection devices as discussed above.

The kit can include a package insert including information concerningthe pharmaceutical compositions and dosage forms in the kit. Generally,such information aids patients and physicians in using the enclosedpharmaceutical compositions and dosage forms effectively and safely. Forexample, the following information regarding a combination of theantigen binding molecule can be supplied in the insert:pharmacokinetics, pharmacodynamics, clinical studies, efficacyparameters, indications and usage, contraindications, warnings,precautions, adverse reactions, overdosage, proper dosage andadministration, how supplied, proper storage conditions, references,manufacturer/distributor information and patent information.

EXAMPLES Example 1 Biochemical Binding Assays

Binding affinities for antigen binding to anti-TIGIT monoclonalantibodies were determined by ELISA. His-tagged recombinant proteins,Mouse or Human TIGIT were coated on Immunolon 384-well plates at aconcentration of 0.5 μg/mL in 1× coating buffer. Antibodies to be testedwere diluted to 1 μM in PBS buffer containing 1% BSA and diluted 3-foldin a 10-point curve. Detection of the antibody binding to the antigenwas performed using biotinylated goat anti-human kappa light chain.Detection of the secondary antibody was determined usingstreptavidin-HRP and TMB reagent. All assays were performed at roomtemperature. Curve-fitting software was used to determine the EC₅₀ foreach antibody. Data from these assays is shown in Tables 1.1-1.3. Lowervalues indicate superior binding activity and the units are in microM.

TABLE 1.1 (ARE) ELISA- ELISA- Goat anti- Human Mouse clone HuKappaTIGIT, 10 pt TIGIT, 10 pt Ab58 3.647        0.6869 0.1695 Ab693.774 >1μM >1μM Ab75 3.778 >1μM >1μM Ab133 3.902 >1μM >1μM Ab177 3.525       0.0283 0.4387 Ab122 3.937        0.1347 >1μM Ab86 3.753       0.2643 0.0838 Ab180 3.741        0.0223 0.0784 Ab83 3.959inconclusive inconclusive Ab26 3.813        0.0533 0.0475 Ab20 3.602      0.033 0.0327 Ab147 3.893 >1μM >1μM Ab12 3.724        0.0277 >1μMAb66 3.825        0.2596 >1μM Ab176 3.61        0.0206 0.1871 Ab96 3.852       0.2106 0.3444 Ab123 3.936      0.43 0.5777 Ab109 3.955 >1μM >1μMAb149 3.175 >1μM 0.052  Ab34 3.638        0.0087 0.105  Ab61 3.842       0.1125 >1μM Ab64 3.851        0.229 inconclusive Ab1053.887 >1μM >1μM Ab108 3.914        0.8345 0.6831 Ab178 3.554       0.0061 0.024  Ab166 3.613        0.0041 0.0104 Ab29 3.788       0.0097 0.041  Ab135 3.873        0.0254 0.0252 Ab171 3.386       0.0346 0.0864 Ab194 3.347        0.0259 0.0706 Ab184 3.397       0.0143 0.0575 Ab164 3.385        0.0154 0.2894 Ab183 3.504       0.0057 0.1102 Ab158 2.994 >1μM 0.1565 Ab55 3.749       1.0230.2907 Ab136 3.962        0.1768 >1μM Ab39 3.736        0.0327 0.0803Ab159 3.076        0.3846 0.1161 Ab151 3.308        0.3766 0.1758 Ab1393.959        0.1302 0.1246 Ab107 3.845 >1μM inconclusive Ab36 3.713       0.0628 0.47   Ab193 3.465        0.0046 >1μM Ab1153.936 >1μM >1μM Ab106 3.94        0.2288 0.1248 Ab138 3.743       0.2340.0586 Ab127 3.732 >1μM >1μM Ab165 3.672        0.0128 0.2285 Ab1553.325        0.0328 0.234  Ab19 3.703        0.0198 0.0648 Ab6 3.698       0.0254 >1μM Ab187 3.356        0.0062 >1μM Ab179 3.418      0.155 0.228  Ab65 3.709 >1μM 0.778  Ab114 4.018 >1μM >1μM Ab1023.927 >1μM >1μM Ab94 4.036        0.0893 0.058  Ab163 3.661       0.0492 0.3167 Ab110 3.785       0.065 0.0619 Ab80 3.885       0.8983 0.478  Ab92 3.859 >1μM >1μM Ab117 3.835        0.00170.0107 Ab162 3.398        0.0018 0.0204 Ab121 3.976 >1μM >1μM Ab1953.507        0.0441 0.1059 Ab84 4.008        0.3919 0.2207 Ab161 3.394       0.1222 0.4079 Ab198 3.528        0.0214 0.0691 Ab24 3.462       0.0359 0.2545 Ab98 3.95        0.0366 0.0219 Ab116 3.845       0.4443 >1μM Ab174 3.723        0.0145 0.1727 Ab196 3.654       0.0037 0.0195 Ab51 3.03        0.0972 0.0798 Ab91 3.977inconclusive 0.242  Ab185 3.343        0.0817 0.1013 Ab23 3.719      0.289 0.0744 Ab7 3.521        0.0146 0.0115 Ab95 3.867       0.3572 0.1001 Ab100 3.756 inconclusive 0.2575 Ab140 3.776inconclusive 0.1734 Ab145 3.946        0.2325 0.0504 Ab150 2.646 >1μM0.0007 Ab168 3.143        0.4759 0.2526 Ab54 3.744        0.0919 0.0215Ab77 3.792 0.1114 Ab43 3.195        0.0479 0.0172 Ab160 3.134       0.4041 0.0264 Ab82 3.882 inconclusive 0.0615 Ab189 3.353       0.0364 0.0529 Ab17 3.576        0.0147 0.014  Ab103 3.926 5000inconclusive Ab18 3.731        0.0453 0.049  Ab130 3.844 inconclusive0.432  Ab132 3.799 >1μM 0.3113 Ab134 3.998 >1μM 0.343  Ab144 3.863 >1μM0.315 

TABLE 1.2 (ARG) ELISA- ELISA- Human Mouse Goat anti- TIGIT, TIGIT, cloneHuKappa 10 pt 10 pt Ab2 3.335 0.0157 >1μM Ab47 3.058 0.0349 0.3614 Ab493.297 0.0276 0.058  Ab31 3.724 0.0125 0.0569 Ab53 3.183 0.0043 0.0076Ab40 2.531 0.0003 >1μM Ab5 3.59 0.0101 0.322  Ab9 3.618 0.0326 0.1814Ab48 3.02 0.0138 0.0418 Ab4 3.462 0.0012 >1μM Ab10 3.547 0.1011 0.0407Ab37 3.819 0.0408 0.2208 Ab33 3.716 0.025 0.0854 Ab42 3.012 0.07650.0605 Ab45 3.226 0.0354 0.048 

TABLE 1.3 (ARV) ELISA- ELISA- Human Mouse Goat anti- TIGIT, TIGIT, cloneHuKappa 10 pt 10 pt Ab44 3.253 0.0135 0.1281 Ab97 3.763 0.2887 >1μM Ab813.878 0.0495 0.3073 Ab188 3.166 0.0093 0.0403 Ab186 3.497 0.0207 0.429 Ab62 3.665 >1μM 0.3612 Ab57 3.839 0.1454 0.3054 Ab192 3.463 0.01240.2952 Ab73 3.736 >1μM 0.2659 Ab60 3.778 0.0798 inconclusive Ab28 3.7010.0075 0.0287 Ab32 3.648 0.0043 0.0147 Ab78 3.779 0.119  >1μM Ab14 3.7230.0201 0.1694 Ab152 3.518 0.0271 >1μM Ab72 3.853 0.0817 0.2347 Ab1373.973 inconclusive 0.0849 Ab128 3.779 inconclusive 0.2646 Ab169 3.4910.1527 0.1099 Ab87 3.783 inconclusive 0.2304 Ab74 3.757 0.1768 0.0419Ab172 3.357 0.0832 0.1078 Ab153 3.255 0.0877 0.0139 Ab120 3.849 >1μM0.2542 Ab13 3.51 0.0431 0.0592 Ab113 3.941 inconclusive inconclusiveAb16 3.609 0.0036 0.0049 Ab56 3.687 0.0196 Ab129 3.847 >1μM >1μM Ab503.191 0.0447 0.0178 Ab90 3.897 inconclusive 0.2034 Ab99 3.938 0.17570.05   Ab3 3.422 0.0586 >1μM Ab148 4.042 0.1681 0.0164 Ab124 3.9050.0343 0.0141 Ab22 3.684 0.0091 0.0051 Ab41 3.025 0.011  0.0095 Ab1193.981 inconclusive 0.2786 Ab157 3.001 0.1654 0.1161 Ab27 3.554 0.01270.0177 Ab15 3.697 0.005  0.0084 Ab191 3.448 0.0449 0.1044 Ab190 3.5430.0021 0.0234 Ab79 3.88 0.0278 0.0866 Ab181 3.258 Ab146 3.967 0.00760.0078 Ab167 3.475 0.0126 0.0612 Ab88 3.986 0.149  0.4074 Ab199 3.3080.0018 0.081  Ab71 3.738 >1μM 0.477  Ab85 4.014 >1μM 0.6825 Ab593.779 >1μM >1μM Ab141 3.74 0.1766 0.1233 Ab68 3.904 0.639  >1μM Ab1433.89 0.0034 0.0057 Ab46 3.418 0.0082 0.095 Ab197 3.462 0.0111 0.0814Ab175 3.684 0.0052 0.0393 Ab156 3.312 >1μM 0.1645 Ab63 3.732 0.09190.1785 Ab11 3.69 0.0902 0.3594 Ab182 3.334 0.1813 0.1997 Ab89 3.869inconclusive inconclusive Ab8 3.699 0.106  0.1493 Ab101 3.89inconclusive 0.535  Ab25 3.504 0.0135 0.0209 Ab154 3.347 0.0908 0.1218Ab21 3.699 0.202  0.1467 Ab111 3.795 inconclusive 0.1855 Ab118 3.9890.392  0.1096 Ab173 3.395 0.0457 0.0649 Ab38 3.65 0.0455 >1μM Ab76 3.9490.0681 0.0657 Ab131 3.917 0.0072 0.3313 Ab1 4 0.0403 0.1807 Ab673.791 >1μM >1μM Ab70 3.896 >1μM >1μM Ab170 3.581 0.1379 >1μM Ab30 3.670.0157 0.1353 Ab93 4.019 0.1221 >1μM Ab142 3.836 0.1085 >1μM Ab1043.899 >1μM >1μM Ab112 3.955 0.7522 0.2131 Ab35 3.811 0.0312 0.3566 Ab1263.889 0.2034 0.0641 Ab125 3.977 0.1273 0.1505

Example 2 Biochemical Competitive Binding

The ability of the antibodies to block polio virus receptor (PVR; akaCD155) binding to the human or the mouse TIGIT extra cellular domain(TIGIT-ECD) was assessed by ELISA. PVR was coated on 384-well Immunolonplates in coating buffer at 0.5 μg/mL. Antibodies were serially dilutedin a 10-point curve starting at 1 μM in 3-fold steps. Human TIGITproteins were biotinylated using the EZ-Link NHS-PEG4-biotin kit (ThermoFisher). The antibodies were pre-incubated with biotinylated human TIGITor mouse TIGIT-Fc at a concentration of 500 ng/mL in 1% BSA in PBST for1 hour. The mixtures of antibodies and receptors were added to thePVR-coated plates for 1 hour. The inhibition of ligand-receptorinteraction for the human TIGIT was detected with streptavidin-HRP at aconcentration of 10 ng/mL and TMB. The inhibition of ligand-receptorinteraction for the mouse TIGIT was detected by ELISA. Data from thesebinding assays is shown in Tables 2.1-2.3. Units are in microM.

TABLE 2.1 (ARE) Competitive Competitive ELISA- ELISA- Human Mouse cloneTIGIT, 10 pt TIGIT, 10 pt Ab58 0.1382 0.2384 Ab69 0.9167 >1 μM Ab750.2715 1.857 Ab133 1.254 >1 μM Ab177 0.1303 0.2831 Ab122 0.7483 >1 μMAb86 0.1243 0.3617 Ab180 0.1276 0.1949 Ab83 inconclusive 0.9737 Ab260.2748 0.2356 Ab20 0.1557 0.1801 Ab147 >1 μM >1 μM Ab12 0.0934 >1 μMAb66 0.279 0.3091 Ab176 0.1252 0.1697 Ab96 0.1926 0.4967 Ab123 0.22921.944 Ab109 0.4441 1.305 Ab149 >1 μM 0.0471 Ab34 0.0552 0.5826 Ab610.3977 0.8403 Ab64 0.1249 0.3621 Ab105 0.573 1.916 Ab108 0.6936 2.819Ab178 0.04 0.0591 Ab166 0.0226 0.028 Ab29 0.0493 0.2798 Ab135 0.14470.0865 Ab171 0.1697 0.1323 Ab194 0.155 0.2223 Ab184 0.1058 0.1206 Ab1640.0753 0.1047 Ab183 0.0751 0.1144 Ab158 >1 μM 0.1315 Ab55 0.255 0.3675Ab136 >1 μM 0.9557 Ab39 0.1213 0.1891 Ab159 0.5386 0.2718 Ab151 0.44530.6308 Ab139 0.249 2.148 Ab107 5000 5000 Ab36 0.1261 0.8038 Ab1930.093 >1 μM Ab115 0.6072 >1 μM Ab106 0.2179 0.1886 Ab138 0.1772 0.252Ab127 0.8486 0.4914 Ab165 0.0891 0.1888 Ab155 0.203 0.5006 Ab19 0.07350.1839 Ab6 0.0639 0.5111 Ab187 0.0817 0.1319 Ab179 0.3039 0.3944 Ab650.435 0.4874 Ab114 0.4728 >1 μM Ab102 0.4836 0.7866 Ab94 0.1157 0.0847Ab163 0.2119 0.1305 Ab110 0.1659 0.1999 Ab80 0.2575 0.2643 Ab92 Ab1170.0385 0.0234 Ab162 0.0433 0.0283 Ab121 0.41 2.066 Ab195 0.2459 0.301Ab84 0.1373 0.257 Ab161 0.372 0.8733 Ab198 0.1292 0.2535 Ab24 0.11751.024 Ab98 0.0447 0.0593 Ab116 0.704 >1 μM Ab174 0.1075 0.085 Ab1960.0493 0.0452 Ab51 0.0754 0.3106 Ab91 inconclusive 0.4574 Ab185 0.33980.1977 Ab23 0.0931 0.1432 Ab7 0.0598 0.0568 Ab95 0.526 0.2019 Ab100 5000inconclusive Ab140 0.6338 0.4787 Ab145 0.4258 0.3346 Ab150 >1 μM 0.0046Ab168 0.8658 0.2572 Ab54 0.1124 0.0729 Ab77 0.5447 0.4125 Ab43 0.19650.0608 Ab160 0.4074 0.2125 Ab82 0.5809 0.1076 Ab189 0.1396 0.1408 Ab170.0529 0.0458 Ab103 inconclusive 1.114 Ab18 0.1906 0.1878 Ab130 >1 μM5000 Ab132 >1 μM 0.771 Ab134 >1 μM 0.8851 Ab144 >1 μM 1.09

TABLE 2.2 (ARG) Competitive Competitive ELISA- ELISA- Human Mouse cloneTIGIT, 10 pt TIGIT, 10 pt Ab2 0.038 >1 μM Ab47 0.4918 0.3799 Ab49 0.1580.2649 Ab31 0.0502 0.2728 Ab53 0.009 0.0353 Ab40 0.0038 >1 μM Ab5 0.03570.3774 Ab9 0.0911 1.005 Ab48 0.1106 0.0647 Ab4 0.0059 >1 μM Ab10 0.0710.0688 Ab37 0.1471 0.2166 Ab33 0.0826 0.5685 Ab42 0.1988 0.1124 Ab45 0.10.1219

TABLE 2.3 (ARV) Competitive Competitive ELISA- ELISA- Human Mouse cloneTIGIT, 10 pt TIGIT, 10 pt Ab44 0.0416 0.2812 Ab97 0.232 1.107 Ab81 0.0620.3523 Ab188 0.0456 0.1 Ab186 0.1016 0.885 Ab62 0.2667 0.9408 Ab570.0566 0.1306 Ab192 0.1592 0.5436 Ab73 0.0999 1.219 Ab60 0.0464 0.2728Ab28 0.0248 0.1435 Ab32 0.0134 0.0507 Ab78 0.1277 1.836 Ab14 0.0590.8418 Ab152 0.1067 1.095 Ab72 0.4462 0.2266 Ab137 inconclusive 0.2111Ab128 inconclusive 0.3249 Ab169 0.4434 0.1726 Ab87 inconclusive 0.3725Ab74 0.1058 0.0589 Ab172 0.3863 0.1174 Ab153 0.1494 0.0691 Ab120 0.4570.3177 Ab13 0.1233 0.1482 Ab113 inconclusive 1.026 Ab16 0.0159 0.0258Ab56 0.0997 0.1266 Ab129 >1 μM 0.1293 Ab50 0.0397 0.0466 Ab90 0.35260.2541 Ab99 0.1653 0.0807 Ab3 0.0235 >1 μM Ab148 0.1738 0.1201 Ab1240.2217 0.0856 Ab22 0.018 0.0242 Ab41 0.0764 0.0447 Ab119 inconclusive0.3888 Ab157 0.4347 0.5118 Ab27 0.047 0.0518 Ab15 0.022 0.04 Ab1910.2782 0.2256 Ab190 0.037 0.0432 Ab79 0.0543 0.0334 Ab181 Ab146 0.04530.0361 Ab167 0.0885 0.0682 Ab88 0.6681 1.364 Ab199 0.0464 0.1109 Ab710.1221 0.5911 Ab85 0.141 0.1534 Ab59 >1 μM >1 μM Ab141 0.215 0.2806 Ab680.2926 0.5568 Ab143 0.0203 0.022 Ab46 0.1883 0.1185 Ab197 0.1104 0.1045Ab175 0.042 0.0533 Ab156 >1 μM 0.0653 Ab63 0.2041 0.1838 Ab11 0.19690.3391 Ab182 0.5126 0.5807 Ab89 inconclusive 0.9985 Ab8 0.3472 0.4284Ab101 inconclusive 5000 Ab25 0.047 0.0602 Ab154 0.3326 0.2508 Ab210.1282 0.3154 Ab111 0.4407 0.7051 Ab118 0.6052 0.3567 Ab173 0.14680.1674 Ab38 0.08 >1 μM Ab76 0.1274 0.0896 Ab131 0.1713 0.116 Ab1 0.08990.6317 Ab67 0.6037 2.581 Ab70 0.4496 1.891 Ab170 0.4011 0.4345 Ab300.084 0.3441 Ab93 0.4337 0.9349 Ab142 0.6591 2.169 Ab104 2.364 1.555Ab112 0.293 0.3211 Ab35 0.1199 0.4375 Ab126 0.3398 0.1827 Ab125 0.11111.395

Example 3 Inhibition of Grb2 Recruitment Assay (Competitive Binding)

YTS cells (NK cell line) were engineered to express human TIGIT fused tothe Alpha portion of beta galactosidase (beta gal) and Grb2 fused to thecomplementary omega portion of beta gal (or vice versa)(YTS_TIGIT/Grb2). 721.221 cells (B-cell line) were engineered to expressPVR (221_PVR). Binding of PRV with TIGIT increases recruitment of Grb2to TIGIT in the YTS cells. YTS cells were plated and then incubated withserial dilutions of antibody for 1.5 hours at 37 degrees C. 221_PVRcells were then added to the YTS cells and co-cultured overnight (16-24hours). The extent of TIGIT binding with Grb2 was detected using achemiluminescence beta gal staining kit and read on a fluorescence platereader to assess reconstitution of active beta gal enzyme. The ratio ofGrb2-TIGIT binding in the absence and presence of antibody wascalculated to determine IC50 of inhibition of Grb2 recruitment. Datafrom these inhibition assays is shown in Tables 3.1-3.4 and units are inmicroM.

TABLE 3.1 (ARE) YTS_hTIGI/hGrbs_EFC_Antagonism, YTS_hTIGIT/hGrb2, clone221_hPVR/ICAM, 11 pt Ab58 Ab69 Ab75 Ab133 Ab177 Ab122 Ab86 Ab180 Ab83Ab26 Ab20 Ab147 Ab12 Ab66 Ab176 Ab96 Ab123 Ab109 Ab149 Ab34 Ab61 Ab64Ab105 Ab108 Ab178 0.3616 Ab166 0.0212 Ab29 Ab135 Ab171 Ab194 Ab184 Ab164Ab183 Ab158 Ab55 Ab136 Ab39 Ab159 Ab151 Ab139 Ab107 Ab36 Ab193 Ab115Ab106 Ab138 Ab127 Ab165 Ab155 Ab19 Ab6 Ab187 Ab179 Ab65 Ab114 Ab102 Ab94Ab163 Ab110 Ab80 Ab92 Ab117 Ab162 0.3645 Ab121 Ab195 Ab84 Ab161 Ab198Ab24 Ab98 Ab116 Ab174 Ab196 Ab51 Ab91 Ab185 Ab23 Ab7 Ab95 Ab100 Ab140Ab145 Ab150 Ab168 Ab54 Ab77 Ab43 Ab160 Ab82 Ab189 Ab17 Ab103 Ab18 Ab130Ab132 Ab134 Ab144

TABLE 3.2 (ARG) YTS_hTIGI/hGrbs_EFC_Antagonism, YTS_hTIGIT/hGrb2, clone221_hPVR/ICAM, 11 pt Ab2 Ab47 Ab49 Ab31 Ab53 0.0303 Ab40 0.0023 Ab5 Ab9Ab48 Ab4 0.0922 Ab10 Ab37 Ab33 Ab42 Ab45

TABLE 3.3 (ARV) YTS_hTIGIT/hGrbs_EFC_Antagonism, YTS_hTIGIT/hGrb2, clone221_hPVR/ICAM, 11 pt Ab44 Ab97 Ab81 Ab188 Ab186 Ab62 Ab57 Ab192 Ab73Ab60 Ab28 0.2034 Ab32 1.407 Ab78 Ab14 Ab152 Ab72 Ab137 Ab128 Ab169 Ab87Ab74 Ab172 Ab153 Ab120 Ab13 Ab113 Ab16 1.744 Ab56 Ab129 Ab50 Ab90 Ab99Ab3 0.1131 Ab148 Ab124 Ab22 0.6079 Ab41 Ab119 Ab157 Ab27 Ab15 Ab191Ab190 Ab79 Ab181 Ab146 Ab167 Ab88 Ab199 Ab71 Ab85 Ab59 Ab141 Ab68 Ab1430.0602 Ab46 0.1593 Ab197 Ab175 0.2877 Ab156 Ab63 Ab11 Ab182 Ab89 Ab8Ab101 Ab25 Ab154 Ab21 Ab111 Ab118 Ab173 Ab38 Ab76 Ab131 0.065 Ab1 Ab67Ab70 Ab170 Ab30 Ab93 Ab142 Ab104 Ab112 Ab35 Ab126 Ab125

Example 4 Cell-Based Binding Assay (Dimerization)

YTS cells were engineered to express both TIGIT fused to the alphaportion of a beta gal and TIGIT fused to the omega portion of a beta gal(YTS_TIGIT/TIGIT). YTS cells were plated and then incubated with serialdilutions of antibody for 1.5 hours at 37 degrees C. 221_PVR cells werethen added to the YTS cells and co-cultured overnight (16-24 hours). Theextent of TIGIT dimerization was detected using a chemiluminescence betagal staining kit and read on a fluorescence plate reader to assessreconstitution of active beta gal enzyme. The ratio of TIGITdimerization in the absence and presence of antibody was calculated todetermine EC50 of induced dimerization. Data from these assays is shownin Tables 4.1-4.3 and units are in microM.

TABLE 4.1 (ARE) YTS_hTIGIT/hTIGIT_EFC, clone YTS_hTIGIT/hTIGIT, 11 ptAb58 Ab69 Ab75 Ab133 Ab177 Ab122 Ab86 Ab180 Ab83 Ab26 Ab20 Ab147 Ab12Ab66 Ab176 Ab96 0.3209 Ab123 Ab109 Ab149 Ab34 Ab61 Ab64 0.7377 Ab105Ab108 Ab178 0.0487 Ab166 0.0147 Ab29 Ab135 Ab171 Ab194 Ab184 Ab164 Ab183Ab158 Ab55 0.2214 Ab136 Ab39 Ab159 Ab151 Ab139 Ab107 Ab36 Ab193 Ab115Ab106 Ab138 Ab127 Ab165 Ab155 Ab19 Ab6 Ab187 Ab179 Ab65 Ab114 Ab102 Ab94Ab163 Ab110 0.3595 Ab80 Ab92 Ab117 Ab162 >1 μM Ab121 Ab195 Ab84 Ab161Ab198 Ab24 Ab98 Ab116 Ab174 Ab196 Ab51 0.0408 Ab91 Ab185 Ab23 Ab7 Ab95Ab100 Ab140 Ab145 Ab150 Ab168 Ab54 Ab77 Ab43 Ab160 Ab82 Ab189 Ab17 Ab103Ab18 Ab130 Ab132 Ab134 Ab144

TABLE 4.2 (ARG) YTS_hTIGIT/hTIGIT_EFC, clone YTS_hTIGIT/hTIGIT, 11 ptAb2 Ab47 Ab49 Ab31 Ab53 0.0027 Ab40 0.0095 Ab5 Ab9 Ab48 0.4772 Ab4 Ab100.0572 Ab37 Ab33 Ab42 Ab45

TABLE 4.3 (ARV) YTS_hTIGIT/hTIGIT_EFC, clone YTS_hTIGIT/hTIGIT, 11 ptAb44 Ab97 Ab81 Ab188 Ab186 Ab62 Ab57 0.1528 Ab192 Ab73 Ab60 0.404 Ab28Ab32 Ab78 Ab14 Ab152 Ab72 Ab137 Ab128 Ab169 Ab87 Ab74 0.0019 Ab172 Ab153Ab120 Ab13 Ab113 Ab16 Ab56 Ab129 Ab50 Ab90 0.0074 Ab99 0.154 Ab3 Ab148Ab124 0.3928 Ab22 0.0403 Ab41 Ab119 Ab157 Ab27 Ab15 Ab191 Ab190 Ab79Ab181 Ab146 Ab167 Ab88 Ab199 Ab71 Ab85 Ab59 Ab141 Ab68 Ab143 0.0047 Ab460.0056 Ab197 Ab175 0.0898 Ab156 Ab63 Ab11 Ab182 Ab89 Ab8 Ab101 Ab25Ab154 Ab21 Ab111 Ab118 Ab173 Ab38 Ab76 Ab131 0.0172 Ab1 Ab67 Ab70 Ab170Ab30 Ab93 Ab142 Ab104 Ab112 Ab35 Ab126 0.0375 Ab125

Example 5 Method of Identification of TIGIT Antibodies from PhageDisplay Screening

In order to generate the above antibodies, phage displayed humanantibody libraries were composed of diversified monovalent Fabsdisplayed as pIII fusions on the surface of M13 bacteriophage.Monovalent Fabs comprise human heavy chain frameworks, including the CH1region, diversified in CDRs 1, 2, and 3 and complexed with a defined setof human antibody light chains.

Phagemid expression of monovalent Fab libraries was accomplished bystandard methods. TG-1 cells transformed with expression plasmids weregrown to mid log (O.D. 600.about.0.3) in 2-YT media supplemented with100 mcg/ml ampicillin and 2% glucose repression and then infected withm13K07 helper phage and grown overnight in 2-YT media supplemented with100 mcg ampicillin, 70 mcg/ml kanamycin, and 200 micromolar IPTG. Phagecontaining supernatants were precipitated using polyethylene glycol andPBS resuspended phage were used to pan on immobilized TIGIT.

Panning of the libraries was performed by using recombinant solubleextracellular domains of TIGIT (Sino Biologicssor R&D Systems)immobilized on the wells of a microtiter dish or biotinylated TIGITimmobilized on streptavidin derivatized magnetic beads (Dynal-LifeTechnologies).

In the plate-based format, Immulon 4HBX ELISA plates were coated withTIGIT. The TIGIT sequences used can be found in FIG. 4. Plates were thenblocked in PBS, 0.05% Tween 20, 4% non-fat dried milk for 1 hour.Approximately 10¹²-10¹³ phage were blocked as above and applied to thetarget coated wells. Following a two hour incubation, the wells werewashed using PBS, 0.05% Tween 20. Phage were then eluted 0.2MGlycine-HCl, pH 2.2, 1 mg/ml BSA. Eluted phage were neutralized using 2MTris base. The eluted phage were subjected to additional rounds ofamplification and panning until the titer of the phage eluted from theTIGIT coated wells exceeded the titer eluted from uncoated, blockedwells.

In bead based panning, TIGIT was biotinylated using aNHS-PEO₄-biotinylation kit (Pierce). The biotinylated protein was thenimmobilized on magnetic streptavidin beads (Dynal-Life Technologies)Panning was carried out essentially as described above for plate basedpanning except that PBS, 0.05% Tween 20, 1% BSA was used as the blockingagent. Beads were collected magnetically following the initial phagebinding and after each wash step.

To identify phage clones that encoded TIGIT-binding monovalent Fabs, aportion of the eluted phage were used to infect E. coli HB2151 allowingexpression of periplasmic phage-encoded monovalent Fabs. Individualclones were picked into deep-well plates and grown overnight in 2YTcontaining ampicillin and 0.2 mM IPTG. Bacteria were lysed in BPERII andthe lysates were applied to TIGIT coated plates. Following washing,binding of antibodies was detected using an HRP-conjugated anti-humankappa and lambda light chain antibody (Bethyl). Daughter plates werealso inoculated and grown in 2YT-Amp-glucose for Sanger-based sequencingto determine the antibody heavy and light chain sequences.

Example 6

Presented in Table 6.1 are the results noted above, as well as theresults for IgGs made using the corresponding CDRs sequences for thenoted constructs from Example 5. Table 6.1 also provides data showingantagonism of the receptor in an assay that uses the same Grb2/TIGITbeta gal set up as provided in the above example 3, but the valueprovided is an EC50 value of Grb2 binding increase by the antibody in anassay replacing the 221_PVR cells with wild-type 221 cells (cells thatdon't express PVR). The point changes noted in the fourth columnrepresent variants. Where no point change is present, then the IgGcontained the same sequence as noted in the sequence for the designatedantibody number.

TABLE 6.1 YTS_ YTS_ hTIGI/ YTS_ hTIGI/ hGrbs_ hTIGIT/ hGrbs_ EFC_hTIGIT_ EFC_ Antagonism, YTS_ EFC, Agonism, YTS_ hTIGIT/ YTS_ YTS_hTIGIT/ hTIGIT_ hTIGIT/ Point Comp. Comp. hTIGIT/ hGrb2, EFC, hTIGIT,changes ELISA- ELISA- ELISA- ELISA- hGrb2, 221_ YTS_ 221_ Name withHuman Mouse Human Mouse 221_ hPVR/ hTIGIT/ hPVR/ of IgG in TIGIT, TIGIT,TIGIT, TIGIT, WT, ICAM, hTIGIT, ICAM, Ab IgG used CDRs 10 pt 10 pt 10 pt10 pt 11 pt 11 pt 11 pt M, 11 pt Ab1 0.0403 0.1807 0.0899 0.6317 Ab1i1hIgG1 0.0091 >1 μM 0.0007 Ab1i2 mIgG2a Ab1i3 hIgG1s >1 μM 0.1725 0.0024Ab1i4 hIgG1s I100aM Ab1i5 mIgG2a I100aA 0.008 0.0068 0.0028 0.0133 Ab1i6mIgG2a P96A 0.0294 >1 μM 0.0469 >1 μM Ab1i7 mIgG2a S98A 0.0038 0.07290.0161 0.1832 Ab1i8 mIgG2a S98G 0.0017 0.0263 0.0058 0.0993 Ab1i9 mIgG2aV95A 0.0006 0.0023 0.0023 0.009 Ab1i10 mIgG2a V99A 0.0039 0.0151 0.00580.4876 Ab1i11 mIgG2a W100A >1 μM >1 μM >1 μM >1 μM Ab1i12 mIgG2a Y97A >1μM >1 μM >1 μM >1 μM Ab2 0.0157 >1 μM 0.038 >1 μM Ab2i1 hIgG1s Ab30.0586 >1 μM 0.0235 >1 μM 0.0441 0.1131 0.058 Ab3i1 hIgG1 0.002 >1 μM0.0013 >1 μM 4999 0.3842 0.0026 Ab4 0.0012 >1 μM 0.0059 >1 μM >1 μM0.0922 inconclusive 0.0784 Ab4i1 hIgG1 0.0003 >1 μM 0.0014 >1 μMinconclusive 0.0131 0.0038 >1 μM Ab5 0.0101 0.322 0.0357 0.3774 Ab60.0254 >1 μM 0.0639 0.5111 Ab7 0.0146 0.0115 0.0598 0.0568 Ab8 0.1060.1493 0.3472 0.4284 Ab9 0.0326 0.1814 0.0911 1.005 Ab10 0.1011 0.04070.071 0.0688 >1 μM >1 μM 0.0572 Ab10i1 mIgG2a 0.0003 0.0001 0.00560.0012 >1 μM inconclusive inconclusive Ab10i2 hIgG1 0.0003 0.0001 0.00850.0011 inconclusive 0.3896 0.0026 Ab11 0.0902 0.3594 0.1969 0.3391 Ab120.0277 >1 μM 0.0934 >1 μM Ab13 0.0431 0.0592 0.1233 0.1482 Ab14 0.02010.1694 0.059 0.8418 Ab15 0.005 0.0084 0.022 0.04 >1 μM >1 μM >1 μMAb15i1 hIgG1 0.0048 0.0023 0.0022 0.0012 >1 μM >1 μM 0.003 Ab15i2 mIgG2a0.0216 0.0027 0.0109 0.0016 >1 μM 0.2749 0.0117 Ab16 0.0036 0.00490.0159 0.0258 inconclusive 1.744 inconclusive Ab16i1 hIgG1 0.0021 0.00050.0021 0.0004 inconclusive inconclusive 0.0036 Ab16i2 mIgG2a 0.00640.0005 0.0846 0.0041 inconclusive inconclusive 0.008 >1 μM Ab17 0.01470.014 0.0529 0.0458 >1 μM >1 μM inconclusive Ab17i1 hIgG1 0.0005 0.00010.0106 0.0011 0.0012 >1 μM 0.0022 Ab17i2 mIgG2a 0.0017 0.0002 0.04580.0016 inconclusive >1 μM 0.0064 Ab18 0.0453 0.049 0.1906 0.1878 Ab190.0198 0.0648 0.0735 0.1839 Ab20 0.033 0.0327 0.1557 0.1801 Ab21 0.2020.1467 0.1282 0.3154 Ab21i1 hIgG1 >1 μM >1 μM 0.0485 0.2616 >1 μM >1μM >1 μM Ab21i2 mIgG2a 0.0101 0.0101 0.0159 0.148 inconclusiveinconclusive 0.2593 Ab22 0.0091 0.0051 0.018 0.0242 0.0155 0.6079 0.04030.1466 Ab22i1 hIgG1 0.0007 0.0003 0.0015 0.0005 inconclusive 0.15990.0025 Ab22i2 mIgG2a 0.0018 0.0002 0.0383 0.0026 >1 μM >1 μM >1 μM Ab230.289 0.0744 0.0931 0.1432 Ab24 0.0359 0.2545 0.1175 1.024 Ab25 0.01350.0209 0.047 0.0602 Ab26 0.0533 0.0475 0.2748 0.2356 Ab27 0.0127 0.01770.047 0.0518 Ab28 0.0075 0.0287 0.0248 0.1435 inconclusive 0.2034inconclusive Ab28i1 hIgG1 0.0004 0.0027 0.0012 0.0013 inconclusive0.0758 0.0009 Ab28i2 mIgG2a 0.0006 0.0025 0.002 0.0015 inconclusive0.2601 0.0046 Ab29 0.0097 0.041 0.0493 0.2798 >1 μM >1 μM >1 μM Ab29i1hIgG1 0.0021 0.0135 0.0021 0.0035 inconclusive 0.3299 0.0028 Ab29i2mIgG2a 0.0035 0.0139 0.0034 0.0084 inconclusive >1 μM 0.3133 >1 μM Ab300.0157 0.1353 0.084 0.3441 Ab31 0.0125 0.0569 0.0502 0.2728 Ab32 0.00430.0147 0.0134 0.0507 inconclusive 1.407 >1 μM Ab32i1 hIgG1 0.0004 0.00250.0011 0.0014 inconclusive 0.069 0.0024 Ab32i2 mIgG2a 0.0005 0.00210.002 0.0015 inconclusive 0.2425 0.003 Ab33 0.025 0.0854 0.0826 0.5685Ab34 0.0087 0.105 0.0552 0.5826 Ab34i1 hIgG1 0.056 >1 μM 0.00380.0275 >1 μM 0.4964 0.0136 Ab34i2 mIgG2a 0.0242 >1 μM 0.013 0.0859 >1μM >1 μM 0.0276 Ab35 0.0312 0.3566 0.1199 0.4375 Ab36 0.0628 0.47 0.12610.8038 Ab37 0.0408 0.2208 0.1471 0.2166 Ab38 0.0455 >1 μM 0.08 >1 μMAb39 0.0327 0.0803 0.1213 0.1891 Ab40 0.0003 >1 μM 0.0038 >1 μM >1 μM0.0023 0.0095 Ab40i1 hIgG1 0.0003 >1 μM 0.0013 >1 μM >1 μM 0.0002 0.0018Ab40i2 hIgG1 G33S 0.0002 >1 μM 0.002 >1 μM 0.0011 0.1858 0.0037 Ab40i3mIgG2a G33S 0.0002 0.041 0.0037 >1 μM 0.08 0.0098 0.0016 Ab40i4 hIgG1G33S_ 0.0003 0.0025 0.003 0.0111 0.0007 1.629 0.0032 Y52aS Ab40i5 mIgG2aG33S_ 0.0002 0.0024 0.0042 0.0169 0.0358 0.2382 0.0031 Y52aS Ab40i6hIgG1 Y52aS 0.0003 0.037 0.0027 0.0788 0.0014 0.2762 0.0032 Ab40i7mIgG2a Y52aS 0.0002 0.0076 0.003 0.1207 0.0156 0.0163 0.0027 Ab41 0.0110.0095 0.0764 0.0447 >1 μM >1 μM Ab41i1 hIgG1 0.0004 0.0002 0.00130.001 >1 μM >1 μM 0.0018 Ab41i2 mIgG2a 0.0051 0.0003 0.0026 0.0019 >1μM >1 μM 0.0081 Ab42 0.0765 0.0605 0.1988 0.1124 Ab43 0.0479 0.01720.1965 0.0608 Ab44 0.0135 0.1281 0.0416 0.2812 Ab45 0.0354 0.048 0.10.1219 Ab46 0.0082 0.095 0.1883 0.1185 5000 0.1593 0.0056 Ab46i1 hIgG10.002 0.005 0.0011 0.0211 inconclusive 0.0773 0.0005 Ab46i2 mIgG2a0.0006 0.0058 0.0019 0.3671 inconclusive 0.8703 0.0013 Ab47 0.03490.3614 0.4918 0.3799 Ab48 0.0138 0.0418 0.1106 0.0647 inconclusiveinconclusive 0.4772 Ab48i1 hIgG1 0.0002 0.0002 0.0019 0.0015 2499 0.02860.0013 Ab48i2 mIgG2a 0.0002 0.0002 0.0016 0.0019 1999 0.0068 0.0012 Ab490.0276 0.058 0.158 0.2649 Ab50 0.0447 0.0178 0.0397 0.0466 >1 μM >1μM >1 μM Ab50i1 mIgG2a 0.0028 0.0003 0.0653 0.0021 >1 μM inconclusive0.0063 Ab50i2 hIgG1 0.0003 0.0002 0.0066 0.0015 0.0032 inconclusive0.0017 Ab51 0.0972 0.0798 0.0754 0.3106 >1 μM inconclusive 0.0408 Ab52Ab52i1 hIgG1 0.0002 0.0004 0.0025 0.0041 0.0011 0.1899 0.0045 Ab530.0043 0.0076 0.009 0.0353 inconclusive 0.0303 0.0027 Ab53i1 mIgG2a0.0003 0.0004 0.0016 0.0042 1999 0.0259 0.0016 0.0012 Ab53i2 hIgG10.0001 0.0002 0.0006 0.0015 inconclusive 0.0675 0.0011 Ab53i3 hIgG1 S33G0.0008 0.0063 0.0083 0.0185 0.0042 >1 μM 0.0046 Ab53i4 mIgG2a S33G0.0011 0.0046 0.0067 0.0482 0.0185 0.4499 0.0035 Ab53i5 hIgG1 S33G_0.0002 >1 μM 0.0021 >1 μM 0.0057 0.526 0.0023 52aY Ab53i6 mIgG2a S33G_0.0002 0.0323 0.0017 >1 μM 0.0077 0.0363 0.0016 S52aY Ab53i7 hIgG1 S52aY0.0032 >1 μM 0.0363 0.061 0.0681 1.928 0.0061 Ab53i8 mIgG2a S52aY 0.00170.034 0.0125 >1 μM 0.02 >1 μM 0.0029 Ab54 0.0919 0.0215 0.1124 0.0729Ab55 1.023 0.2907 0.255 0.3675 >1 μM >1 μM 0.2214 Ab56 0.0196 0.09970.1266 Ab57 0.1454 0.3054 0.0566 0.1306 >1 μM >1 μM 0.1528 Ab58 0.68690.1695 0.1382 0.2384 Ab59 >1 μM >1 μM >1 μM >1 μM Ab60 0.0798inconclusive 0.0464 0.2728 >1 μM >1 μM 0.404 Ab61 0.1125 >1 μM 0.39770.8403 Ab62 >1 μM 0.3612 0.2667 0.9408 Ab63 0.0919 0.1785 0.20410.1838 >1 μM >1 μM >1 μM Ab64 0.229 inconclusive 0.1249 0.362 >1 μM >1μM 0.7377 Ab65 >1 μM 0.778 0.435 0.4874 Ab66 0.2596 >1 μM 0.279 0.3091Ab67 >1 μM >1 μM 0.6037 2.581 Ab68 0.639 >1 μM 0.2926 0.5568 Ab69 >1μM >1 μM 0.9167 >1 μM Ab70 >1 μM >1 μM 0.4496 1.891 Ab71 >1 μM 0.4770.1221 0.5911 Ab72 0.0817 0.2347 0.4462 0.2266 >1 μM >1 μM >1 μM Ab73 >1μM 0.2659 0.0999 1.219 Ab74 0.1768 0.0419 0.1058 0.0589 0.0008 >1 μM0.0019 Ab75 >1 μM >1 μM 0.2715 1.857 Ab76 0.0681 0.0657 0.1274 0.08960.0504 >1 μM >1 μM Ab77 0.1114 0.5447 0.4125 >1 μM >1 μM >1 μM Ab780.119 >1 μM 0.1277 1.836 Ab79 0.0278 0.0866 0.0543 0.0334 >1 μM >1 μM >1μM Ab80 0.8983 0.478 0.2575 0.2643 >1 μM >1 μM >1 μM Ab81 0.0495 0.30730.062 0.3523 Ab82 inconclusive 0.0615 0.5809 0.1076 >1 μM >1 μM >1 μMAb83 inconclusive inconclusive inconclusive 0.9737 Ab84 0.3919 0.22070.1373 0.257 >1 μM >1 μM >1 μM Ab85 >1 μM 0.6825 0.141 0.1534 Ab860.2643 0.0838 0.1243 0.3617 Ab87 inconclusive 0.2304 inconclusive0.3725 >1 μM >1 μM >1 μM Ab88 0.149 0.4074 0.6681 1.364 Ab89inconclusive inconclusive inconclusive 0.9985 Ab90 inconclusive 0.20340.3526 0.2541 0.0153 >1 μM 0.0074 Ab91 inconclusive 0.242 inconclusive0.4574 Ab92 Ab93 0.1221 >1 μM 0.4337 0.9349 Ab94 0.0893 0.058 0.11570.0847 0.004 >1 μM >1 μM Ab95 0.3572 0.1001 0.526 0.2019 >1 μM >1 μM >1μM Ab96 0.2106 0.3444 0.1926 0.4967 >1 μM >1 μM 0.3209 Ab97 0.2887 >1 μM0.232 1.107 Ab98 0.0366 0.0219 0.0447 0.0593 Ab99 0.1757 0.05 0.16530.0807 >1 μM >1 μM 0.154 Ab100 inconclusive 0.2575 5000 inconclusiveAb101 inconclusive 0.535 inconclusive 5000 >1 μM >1 μM >1 μM Ab102 >1μM >1 μM 0.4836 0.7866 Ab103 5000 inconclusive inconclusive 1.114Ab104 >1 μM >1 μM 2.364 1.555 Ab105 >1 μM >1 μM 0.573 1.916 Ab106 0.22880.1248 0.2179 0.1886 >1 μM >1 μM >1 μM Ab107 >1 μM inconclusive 50005000 Ab108 0.8345 0.6831 0.6936 2.819 Ab109 >1 μM >1 μM 0.4441 1.305Ab110 0.065 0.0619 0.1659 0.1999 >1 μM >1 μM 0.3595 Ab111 inconclusive0.1855 0.4407 0.7051 Ab112 0.7522 0.2131 0.293 0.3211 >1 μM >1 μM >1 μMAb113 inconclusive inconclusive inconclusive 1.026 Ab114 >1 μM >1 μM0.4728 >1 μM Ab115 >1 μM >1 μM 0.6072 >1 μM Ab116 0.4443 >1 μM 0.704 >1μM Ab117 0.0017 0.0107 0.0385 0.0234 >1 μM >1 μM >1 μM Ab118 0.3920.1096 0.6052 0.3567 >1 μM >1 μM >1 μM Ab119 inconclusive 0.2786inconclusive 0.3888 >1 μM >1 μM >1 μM Ab120 >1 μM 0.2542 0.457 0.3177Ab121 >1 μM >1 μM 0.41 2.066 Ab122 0.1347 >1 μM 0.7483 >1 μM Ab123 0.430.5777 0.2292 1.944 Ab124 0.0343 0.0141 0.2217 0.0856 >1 μM >1 μM 0.3928Ab125 0.1273 0.1505 0.1111 1.395 Ab126 0.2034 0.0641 0.3398 0.18270.0258 >1 μM 0.0375 Ab127 >1 μM >1 μM 0.8486 0.4914 Ab128 inconclusive0.2646 inconclusive 0.3249 >1 μM >1 μM >1 μM Ab129 >1 μM >1 μM >1 μM0.1293 Ab130 inconclusive 0.432 >1 μM 5000 >1 μM >1 μM >1 μM Ab1310.0072 0.33113 0.1713 0.116 >1 μM 0.065 0.0172 Ab132 >1 μM 0.3113 >1 μM0.771 Ab133 >1 μM >1 μM 1.254 >1 μM Ab134 >1 μM 0.343 >1 μM 0.8851 Ab1350.0254 0.0252 0.1447 0.0865 >1 μM >1 μM >1 μM Ab136 0.1768 >1 μM >1 μM0.9557 Ab137 inconclusive 0.0849 inconclusive 0.2111 Ab138 0.234 0.05860.1772 0.252 Ab139 0.1302 0.1246 0.249 2.148 Ab140 inconclusive 0.17340.6338 0.4787 Ab141 0.1766 0.1233 0.215 0.2806 Ab142 0.1085 >1 μM 0.65912.169 Ab143 0.0034 0.0057 0.0203 0.022 >1 μM 0.0602 0.0047 Ab144 >1 μM0.315 >1 μM 1.09 Ab145 0.2325 0.0504 0.4258 0.3346 Ab146 0.0076 0.00780.0453 0.0361 >1 μM >1 μM >1 μM Ab147 >1 μM >1 μM >1 μM >1 μM Ab1480.1681 0.0164 0.1738 0.1201 Ab149 >1 μM 0.052 >1 μM 0.0471 Ab150 >1 μM0.0007 >1 μM 0.0046 Ab151 0.3766 0.1758 0.4453 0.6308 Ab152 0.0271 >1 μM0.1067 1.095 Ab153 0.0877 0.0139 0.1494 0.0691 Ab154 0.0908 0.12180.3326 0.2508 Ab155 0.0328 0.234 0.203 0.5006 Ab156 >1 μM 0.1645 >1 μM0.0653 Ab157 0.1654 0.1161 0.4347 0.5118 Ab158 >1 μM 0.1565 >1 μM 0.1315Ab159 0.3846 0.1161 0.5386 0.2718 Ab160 0.4041 0.0264 0.4074 0.2125Ab161 0.1222 0.4079 0.372 0.8733 Ab162 0.0018 0.0204 0.0433 0.0283 >1 μM0.3645 >1 μM Ab163 0.0492 0.3167 0.2119 0.1305 Ab164 0.0154 0.28940.0753 0.1047 Ab165 0.0128 0.2285 0.0891 0.1888 Ab166 0.0041 0.01040.0226 0.028 >1 μM 0.0212 0.0147 Ab167 0.0126 0.0612 0.0885 0.0682 Ab1680.4759 0.2526 0.8658 0.2572 Ab169 0.1527 0.1099 0.4434 0.1726 Ab1700.1379 >1 μM 0.4011 0.4345 Ab171 0.0346 0.0864 0.1697 0.1323 Ab1720.0832 0.1078 0.3863 0.1174 Ab173 0.0457 0.0649 0.1468 0.1674 Ab1740.0145 0.1727 0.1075 0.085 Ab175 0.0052 0.0393 0.042 0.0533 >1 μM 0.28770.0898 Ab176 0.0206 0.1871 0.1252 0.1697 Ab177 0.0283 0.4387 0.13030.2831 Ab178 0.0061 0.024 0.04 0.0591 >1 μM 0.3616 0.0487 Ab179 0.1550.228 0.3039 0.3944 Ab180 0.0223 0.0784 0.1276 0.1949 Ab181 Ab182 0.1830.1997 0.5126 0.5807 Ab183 0.0057 0.1102 0.0751 0.1144 Ab184 0.01430.0575 0.1058 0.1206 Ab185 0.0817 0.1013 0.3398 0.1977 Ab186 0.02070.429 0.1016 0.885 Ab187 0.0062 >1 μM 0.0817 0.1319 Ab188 0.0093 0.04030.0456 0.1 Ab189 0.0364 0.0529 0.1396 0.1408 Ab190 0.0021 0.0234 0.0370.0432 Ab191 0.0449 0.1044 0.2782 0.2256 Ab192 0.0124 0.2952 0.15920.5436 Ab193 0.0046 >1 μM 0.093 >1 μM Ab194 0.0259 0.0706 0.155 0.2223Ab195 0.0441 0.1059 0.2459 0.301 Ab196 0.0037 0.0195 0.0493 0.0452 Ab1970.0111 0.0814 0.1104 0.1045 Ab198 0.0214 0.0691 0.1292 0.2535 Ab1990.0018 0.081 0.0464 0.1109

In some embodiments, any one or more of the alternative CDRs provided asdesignated in column 4 of table 6.1 can be used for any of the antigenbinding molecules or methods related thereto as provided herein. In someembodiments, any one or more of the IgG constructs provided in Table 6.1can be employed as a construct, therapeutic, within a conjugate and/orin a method of treatment.

In some embodiments, an isolated antigen binding molecule (such as afull length antibody or antigen binding fragment thereof) can compriseany one or more of a CDR within any of SEQ ID NO. 1-SEQ ID NO: 97, SEQID NO: 195-SEQ ID NO: 209, SEQ ID NO: 225-SEQ ID NO: 310, SEQ ID NO:98-SEQ ID NO: 194, SEQ ID NO: 210-SEQ ID NO: 224, or SEQ ID NO: 311-SEQID NO: 396 as shown in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K,2L, 2M, 2N, 2O, 2P, 2Q, 2R, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K,or 3L. In some embodiments, an isolated antigen binding molecule thatcompetes for binding to human TIGIT with an antibody comprises all 6CDRs from a single clone in any one of SEQ ID NO. 1-SEQ ID NO: 97, SEQID NO: 195-SEQ ID NO: 209, SEQ ID NO: 225-SEQ ID NO: 310, SEQ ID NO:98-SEQ ID NO: 194, SEQ ID NO: 210-SEQ ID NO: 224, or SEQ ID NO: 311-SEQID NO: 396 as shown in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K,2L, 2M, 2N, 2O, 2P, 2Q, 2R, 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K,or 3L. In some embodiments, an antigen binding molecule that competeswith one of the above constructs can instead be employed.

In some embodiments, an isolated antigen binding molecule that competesfor binding to human TIGIT with an antibody comprises a heavy variableregion (SEQ ID NO. 1-SEQ ID NO: 97, SEQ ID NO: 195-SEQ ID NO: 209, SEQID NO: 225-SEQ ID NO: 310) and a light chain variable region (SEQ ID NO:98-SEQ ID NO: 194, SEQ ID NO: 210-SEQ ID NO: 224, or SEQ ID NO: 311-SEQID NO: 396) from a single clone identified in any one of FIG. 2A, 2B,2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain CDR1 comprising the amino acidsequence of any one of the HCDR1s in SEQ ID NO: 397, SEQ ID NO: 403. SEQID NO: 409, SEQ ID NO: 415, SEQ ID NO: 421, SEQ ID NO: 427, SEQ ID NO:433, SEQ ID NO: 439, SEQ ID NO: 445, SEQ ID NO: 451, SEQ ID NO: 457, SEQID NO: 463, SEQ ID NO: 469, SEQ ID NO: 475, SEQ ID NO: 481, SEQ ID NO:487, SEQ ID NO: 493, SEQ ID NO: 499, SEQ ID NO: 505, SEQ ID NO: 511, SEQID NO: 517, SEQ ID NO: 523, SEQ ID NO: 529, SEQ ID NO: 535, SEQ ID NO:541, SEQ ID NO: 547, SEQ ID NO: 553, SEQ ID NO: 559, SEQ ID NO: 565, SEQID NO: 571, SEQ ID NO: 577, SEQ ID NO: 583, SEQ ID NO: 589, SEQ ID NO:595, SEQ ID NO: 601, SEQ ID NO: 607, SEQ ID NO: 613, SEQ ID NO: 619, SEQID NO: 625, SEQ ID NO: 631, SEQ ID NO: 637, SEQ ID NO: 643, SEQ ID NO:649, SEQ ID NO: 655, SEQ ID NO: 661, SEQ ID NO: 667, SEQ ID NO: 673, SEQID NO: 679, SEQ ID NO: 685, SEQ ID NO: 691, SEQ ID NO: 697, SEQ ID NO:703, SEQ ID NO: 709, SEQ ID NO: 715, SEQ ID NO: 721, SEQ ID NO: 727, SEQID NO: 733, SEQ ID NO: 739, SEQ ID NO: 745, SEQ ID NO: 751, SEQ ID NO:757, SEQ ID NO: 763, SEQ ID NO: 769, SEQ ID NO: 775, SEQ ID NO: 781, SEQID NO: 787, SEQ ID NO: 793, SEQ ID NO: 799, SEQ ID NO: 805, SEQ ID NO:811, SEQ ID NO: 817, SEQ ID NO: 823, SEQ ID NO: 829, SEQ ID NO: 835, SEQID NO: 841, SEQ ID NO: 847, SEQ ID NO: 853, SEQ ID NO: 859, SEQ ID NO:865, SEQ ID NO: 871, SEQ ID NO: 877, SEQ ID NO: 883, SEQ ID NO: 889, SEQID NO: 895, SEQ ID NO: 901, SEQ ID NO: 907, SEQ ID NO: 913, SEQ ID NO:919, SEQ ID NO: 925, SEQ ID NO: 931, SEQ ID NO: 937, SEQ ID NO: 943, SEQID NO: 949, SEQ ID NO: 955, SEQ ID NO: 961, SEQ ID NO: 967, SEQ ID NO:973, SEQ ID NO: 979, SEQ ID NO: 985, SEQ ID NO: 991, SEQ ID NO: 997, SEQID NO: 1003, SEQ ID NO: 1009, SEQ ID NO: 1015, SEQ ID NO: 1021, SEQ IDNO: 1027, SEQ ID NO: 1033, SEQ ID NO: 1039, SEQ ID NO: 1045, SEQ ID NO:1051, SEQ ID NO: 1057, SEQ ID NO: 1063, SEQ ID NO: 1069, SEQ ID NO:1075, SEQ ID NO: 1081, SEQ ID NO: 1087, SEQ ID NO: 1093, SEQ ID NO:1099, SEQ ID NO: 1105, SEQ ID NO: 1111, SEQ ID NO: 1117, SEQ ID NO:1123, SEQ ID NO: 1129, SEQ ID NO: 1135, SEQ ID NO: 1141, SEQ ID NO:1147, SEQ ID NO: 1153, SEQ ID NO: 1159, SEQ ID NO: 1165, SEQ ID NO:1171, SEQ ID NO: 1177, SEQ ID NO: 1183, SEQ ID NO: 1189, SEQ ID NO:1195, SEQ ID NO: 1201, SEQ ID NO: 1207, SEQ ID NO: 1213, SEQ ID NO:1219, SEQ ID NO: 1225, SEQ ID NO: 1231, SEQ ID NO: 1237, SEQ ID NO:1243, SEQ ID NO: 1249, SEQ ID NO: 1255, SEQ ID NO: 1261, SEQ ID NO:1267, SEQ ID NO: 1273, SEQ ID NO: 1279, SEQ ID NO: 1285, SEQ ID NO:1291, SEQ ID NO: 1297, SEQ ID NO: 1303, SEQ ID NO: 1309, SEQ ID NO:1315, SEQ ID NO: 1321, SEQ ID NO: 1327, SEQ ID NO: 1333, SEQ ID NO:1339, SEQ ID NO: 1345, SEQ ID NO: 1351, SEQ ID NO: 1357, SEQ ID NO:1363, SEQ ID NO: 1369, SEQ ID NO: 1375, SEQ ID NO: 1381, SEQ ID NO:1387, SEQ ID NO: 1393, SEQ ID NO: 1399, SEQ ID NO: 1405, SEQ ID NO:1411, SEQ ID NO: 1417, SEQ ID NO: 1423, SEQ ID NO: 1429, SEQ ID NO:1435, SEQ ID NO: 1441, SEQ ID NO: 1447, SEQ ID NO: 1453, SEQ ID NO:1459, SEQ ID NO: 1465, SEQ ID NO: 1471, SEQ ID NO: 1477, SEQ ID NO:1483, SEQ ID NO: 1489, SEQ ID NO: 1495, SEQ ID NO: 1501, SEQ ID NO:1507, SEQ ID NO: 1513, SEQ ID NO: 1519, SEQ ID NO: 1593, SEQ ID NO: 1525SEQ ID NO: 1531, SEQ ID NO: 1537, SEQ ID NO: 1543, SEQ ID NO: 1549, SEQID NO: 1555, SEQ ID NO: 1561, SEQ ID NO: 1567, SEQ ID NO: 1573, SEQ IDNO: 1579, or SEQ ID NO: 1585 as shown in FIG. 3A, 3B, 3C, 3D, 3E, 3F,3G, 3H, 3I, 3J, 3K, or 3L, a heavy chain CDR2 comprising the amino acidsequence of any one of the HCDR2s in SEQ ID NO: 398, SEQ ID NO: 404, SEQID NO: 410, SEQ ID NO: 416, SEQ ID NO: 422, SEQ ID NO: 428, SEQ ID NO:434, SEQ ID NO: 440, SEQ ID NO: 446, SEQ ID NO: 452, SEQ ID NO: 458, SEQID NO: 464, SEQ ID NO: 470, SEQ ID NO: 476, SEQ ID NO: 482, SEQ ID NO:488, SEQ ID NO: 494, SEQ ID NO: 500, SEQ ID NO: 506, SEQ ID NO: 512, SEQID NO: 518, SEQ ID NO: 524, SEQ ID NO: 530, SEQ ID NO: 536, SEQ ID NO:542, SEQ ID NO: 548, SEQ ID NO: 554, SEQ ID NO: 560, SEQ ID NO: 566, SEQID NO: 572, SEQ ID NO: 578, SEQ ID NO: 584, SEQ ID NO: 590, SEQ ID NO:596, SEQ ID NO: 602, SEQ ID NO: 608, SEQ ID NO: 614, SEQ ID NO: 620, SEQID NO: 626, SEQ ID NO: 632, SEQ ID NO: 638, SEQ ID NO: 644, SEQ ID NO:650, SEQ ID NO: 656, SEQ ID NO: 662, SEQ ID NO: 668, SEQ ID NO: 674, SEQID NO: 680, SEQ ID NO: 686, SEQ ID NO: 692, SEQ ID NO: 698, SEQ ID NO:704, SEQ ID NO: 710, SEQ ID NO: 716, SEQ ID NO: 722, SEQ ID NO: 728, SEQID NO: 734, SEQ ID NO: 740, SEQ ID NO: 746, SEQ ID NO: 752, SEQ ID NO:758, SEQ ID NO: 764, SEQ ID NO: 770, SEQ ID NO: 776, SEQ ID NO: 782, SEQID NO: 788, SEQ ID NO: 794, SEQ ID NO: 800, SEQ ID NO: 806, SEQ ID NO:812, SEQ ID NO: 818, SEQ ID NO: 824, SEQ ID NO: 830, SEQ ID NO: 836, SEQID NO: 842, SEQ ID NO: 848, SEQ ID NO: 854, SEQ ID NO: 860, SEQ ID NO:866, SEQ ID NO: 872, SEQ ID NO: 878, SEQ ID NO: 884, SEQ ID NO: 890, SEQID NO: 896, SEQ ID NO: 902, SEQ ID NO: 908, SEQ ID NO: 914, SEQ ID NO:920, SEQ ID NO: 926, SEQ ID NO: 932, SEQ ID NO: 938, SEQ ID NO: 944, SEQID NO: 950, SEQ ID NO: 956, SEQ ID NO: 962, SEQ ID NO: 968, SEQ ID NO:974, SEQ ID NO: 980, SEQ ID NO: 986, SEQ ID NO: 992, SEQ ID NO: 998, SEQID NO: 1004, SEQ ID NO: 1010, SEQ ID NO: 1016, SEQ ID NO: 1022, SEQ IDNO: 1028, SEQ ID NO: 1034, SEQ ID NO: 1040, SEQ ID NO: 1046, SEQ ID NO:1052, SEQ ID NO: 1058, SEQ ID NO: 1064, SEQ ID NO: 1070, SEQ ID NO:1076, SEQ ID NO: 1082, SEQ ID NO: 1088, SEQ ID NO: 1094, SEQ ID NO:1100, SEQ ID NO: 1106, SEQ ID NO: 1112, SEQ ID NO: 1118, SEQ ID NO:1124, SEQ ID NO: 1130, SEQ ID NO: 1136, SEQ ID NO: 1142, SEQ ID NO:1148, SEQ ID NO: 1154, SEQ ID NO: 1160, SEQ ID NO: 1166, SEQ ID NO:1172, SEQ ID NO: 1178, SEQ ID NO: 1184, SEQ ID NO: 1190, SEQ ID NO:1196, SEQ ID NO: 1202, SEQ ID NO: 1208, SEQ ID NO: 1214, SEQ ID NO:1220, SEQ ID NO: 1226, SEQ ID NO: 1232, SEQ ID NO: 1238, SEQ ID NO:1244, SEQ ID NO: 1250, SEQ ID NO: 1256, SEQ ID NO: 1262, SEQ ID NO:1268, SEQ ID NO: 1274, SEQ ID NO: 1280, SEQ ID NO: 1286, SEQ ID NO:1292, SEQ ID NO: 1298, SEQ ID NO: 1304, SEQ ID NO: 1310, SEQ ID NO:1316, SEQ ID NO: 1322, SEQ ID NO: 1328, SEQ ID NO: 1334, SEQ ID NO:1340, SEQ ID NO: 1346, SEQ ID NO: 1352, SEQ ID NO: 1358, SEQ ID NO:1364, SEQ ID NO: 1370, SEQ ID NO: 1376, SEQ ID NO: 1382, SEQ ID NO:1388, SEQ ID NO: 1394, SEQ ID NO: 1400, SEQ ID NO: 1406, SEQ ID NO:1412, SEQ ID NO: 1418, SEQ ID NO: 1424, SEQ ID NO: 1430, SEQ ID NO:1436, SEQ ID NO: 1442, SEQ ID NO: 1448, SEQ ID NO: 1454, SEQ ID NO:1460, SEQ ID NO: 1466, SEQ ID NO: 1472, SEQ ID NO: 1478, SEQ ID NO:1484, SEQ ID NO: 1490, SEQ ID NO: 1496, SEQ ID NO: 1502, SEQ ID NO:1508, SEQ ID NO: 1514, SEQ ID NO: 1520, SEQ ID NO: 1594, SEQ ID NO:1526, SEQ ID NO: 1532, SEQ ID NO: 1538, SEQ ID NO: 1544, SEQ ID NO:1550, SEQ ID NO: 1556, SEQ ID NO: 1562, SEQ ID NO: 1568, SEQ ID NO:1574, SEQ ID NO: 1580, or SEQ ID NO: 1586 as shown in in FIG. 3A, 3B,3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, and a heavy chain CDR3comprising the amino acid sequence of any one of the HCDR3s in SEQ IDNO: 399, SEQ ID NO: 405, SEQ ID NO: 411, SEQ ID NO: 417, SEQ ID NO: 423,SEQ ID NO: 429, SEQ ID NO: 435, SEQ ID NO: 441, SEQ ID NO: 447, SEQ IDNO: 453, SEQ ID NO: 459, SEQ ID NO: 465, SEQ ID NO: 471, SEQ ID NO: 477,SEQ ID NO: 483, SEQ ID NO: 489, SEQ ID NO: 495, SEQ ID NO: 501, SEQ IDNO: 507, SEQ ID NO: 513, SEQ ID NO: 519, SEQ ID NO: 525, SEQ ID NO: 531,SEQ ID NO: 537, SEQ ID NO: 543, SEQ ID NO: 549, SEQ ID NO: 555, SEQ IDNO: 561, SEQ ID NO: 567, SEQ ID NO: 573, SEQ ID NO: 579, SEQ ID NO: 585,SEQ ID NO: 591, SEQ ID NO: 597, SEQ ID NO: 603, SEQ ID NO: 609, SEQ IDNO: 615, SEQ ID NO: 621, SEQ ID NO: 627, SEQ ID NO: 633, SEQ ID NO: 639,SEQ ID NO: 645, SEQ ID NO: 651, SEQ ID NO: 657, SEQ ID NO: 663, SEQ IDNO: 669, SEQ ID NO: 675, SEQ ID NO: 681, SEQ ID NO: 687, SEQ ID NO: 693,SEQ ID NO: 699, SEQ ID NO: 705, SEQ ID NO: 711, SEQ ID NO: 717, SEQ IDNO: 723, SEQ ID NO: 729, SEQ ID NO: 735, SEQ ID NO: 741, SEQ ID NO: 747,SEQ ID NO: 753, SEQ ID NO: 759, SEQ ID NO: 765, SEQ ID NO: 771, SEQ IDNO: 777, SEQ ID NO: 783, SEQ ID NO: 789, SEQ ID NO: 795, SEQ ID NO: 801,SEQ ID NO: 807, SEQ ID NO: 813, SEQ ID NO: 819, SEQ ID NO: 825, SEQ IDNO: 831, SEQ ID NO: 837, SEQ ID NO: 843, SEQ ID NO: 849, SEQ ID NO: 855,SEQ ID NO: 861, SEQ ID NO: 867, SEQ ID NO: 873, SEQ ID NO: 879, SEQ IDNO: 885, SEQ ID NO: 891, SEQ ID NO: 897, SEQ ID NO: 903, SEQ ID NO: 909,SEQ ID NO: 915, SEQ ID NO: 921, SEQ ID NO: 927, SEQ ID NO: 933, SEQ IDNO: 939, SEQ ID NO: 945, SEQ ID NO: 951, SEQ ID NO: 957, SEQ ID NO: 963,SEQ ID NO: 969, SEQ ID NO: 975, SEQ ID NO: 981, SEQ ID NO: 987, SEQ IDNO: 993, SEQ ID NO: 999, SEQ ID NO: 1005, SEQ ID NO: 1011, SEQ ID NO:1017, SEQ ID NO: 1023, SEQ ID NO: 1029, SEQ ID NO: 1035, SEQ ID NO:1041, SEQ ID NO: 1047, SEQ ID NO: 1053, SEQ ID NO: 1059, SEQ ID NO:1065, SEQ ID NO: 1071, SEQ ID NO: 1077, SEQ ID NO: 1083, SEQ ID NO:1089, SEQ ID NO: 1095, SEQ ID NO: 1101, SEQ ID NO: 1107, SEQ ID NO:1113, SEQ ID NO: 1119, SEQ ID NO: 1125, SEQ ID NO: 1131, SEQ ID NO:1137, SEQ ID NO: 1143, SEQ ID NO: 1149, SEQ ID NO: 1155, SEQ ID NO:1161, SEQ ID NO: 1167, SEQ ID NO: 1173, SEQ ID NO: 1179, SEQ ID NO:1185, SEQ ID NO: 1191, SEQ ID NO: 1197, SEQ ID NO: 1203, SEQ ID NO:1209, SEQ ID NO: 1215, SEQ ID NO: 1221, SEQ ID NO: 1227, SEQ ID NO:1233, SEQ ID NO: 1239, SEQ ID NO: 1245, SEQ ID NO: 1251, SEQ ID NO:1257, SEQ ID NO: 1263, SEQ ID NO: 1269, SEQ ID NO: 1275, SEQ ID NO:1281, SEQ ID NO: 1287, SEQ ID NO: 1293, SEQ ID NO: 1299, SEQ ID NO:1305, SEQ ID NO: 1311, SEQ ID NO: 1317, SEQ ID NO: 1323, SEQ ID NO:1329, SEQ ID NO: 1335, SEQ ID NO: 1341, SEQ ID NO: 1347, SEQ ID NO:1353, SEQ ID NO: 1359, SEQ ID NO: 1365, SEQ ID NO: 1371, SEQ ID NO:1377, SEQ ID NO: 1383, SEQ ID NO: 1389, SEQ ID NO: 1395, SEQ ID NO:1401, SEQ ID NO: 1407, SEQ ID NO: 1413, SEQ ID NO: 1419, SEQ ID NO:1425, SEQ ID NO: 1431, SEQ ID NO: 1437, SEQ ID NO: 1443, SEQ ID NO:1449, SEQ ID NO: 1455, SEQ ID NO: 1461, SEQ ID NO: 1467, SEQ ID NO:1473, SEQ ID NO: 1479, SEQ ID NO: 1485, SEQ ID NO: 1491, SEQ ID NO:1497, SEQ ID NO: 1503, SEQ ID NO: 1509, SEQ ID NO: 1515, SEQ ID NO:1521, SEQ ID NO: 1595, SEQ ID NO: 1527, SEQ ID NO: 1533, SEQ ID NO:1539, SEQ ID NO: 1545, SEQ ID NO: 1551, SEQ ID NO: 1557, SEQ ID NO:1563, SEQ ID NO: 1569, SEQ ID NO: 1575, SEQ ID NO: 1581, or SEQ ID NO:1587 as shown in in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or3L.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain CDR1 comprising the amino acidsequence of any one of the HCDR1s in SEQ ID NO: 397, SEQ ID NO: 403. SEQID NO: 409, SEQ ID NO: 415, SEQ ID NO: 421, SEQ ID NO: 427, SEQ ID NO:433, SEQ ID NO: 439, SEQ ID NO: 445, SEQ ID NO: 451, SEQ ID NO: 457, SEQID NO: 463, SEQ ID NO: 469, SEQ ID NO: 475, SEQ ID NO: 481, SEQ ID NO:487, SEQ ID NO: 493, SEQ ID NO: 499, SEQ ID NO: 505, SEQ ID NO: 511, SEQID NO: 517, SEQ ID NO: 523, SEQ ID NO: 529, SEQ ID NO: 535, SEQ ID NO:541, SEQ ID NO: 547, SEQ ID NO: 553, SEQ ID NO: 559, SEQ ID NO: 565, SEQID NO: 571, SEQ ID NO: 577, SEQ ID NO: 583, SEQ ID NO: 589, SEQ ID NO:595, SEQ ID NO: 601, SEQ ID NO: 607, SEQ ID NO: 613, SEQ ID NO: 619, SEQID NO: 625, SEQ ID NO: 631, SEQ ID NO: 637, SEQ ID NO: 643, SEQ ID NO:649, SEQ ID NO: 655, SEQ ID NO: 661, SEQ ID NO: 667, SEQ ID NO: 673, SEQID NO: 679, SEQ ID NO: 685, SEQ ID NO: 691, SEQ ID NO: 697, SEQ ID NO:703, SEQ ID NO: 709, SEQ ID NO: 715, SEQ ID NO: 721, SEQ ID NO: 727, SEQID NO: 733, SEQ ID NO: 739, SEQ ID NO: 745, SEQ ID NO: 751, SEQ ID NO:757, SEQ ID NO: 763, SEQ ID NO: 769, SEQ ID NO: 775, SEQ ID NO: 781, SEQID NO: 787, SEQ ID NO: 793, SEQ ID NO: 799, SEQ ID NO: 805, SEQ ID NO:811, SEQ ID NO: 817, SEQ ID NO: 823, SEQ ID NO: 829, SEQ ID NO: 835, SEQID NO: 841, SEQ ID NO: 847, SEQ ID NO: 853, SEQ ID NO: 859, SEQ ID NO:865, SEQ ID NO: 871, SEQ ID NO: 877, SEQ ID NO: 883, SEQ ID NO: 889, SEQID NO: 895, SEQ ID NO: 901, SEQ ID NO: 907, SEQ ID NO: 913, SEQ ID NO:919, SEQ ID NO: 925, SEQ ID NO: 931, SEQ ID NO: 937, SEQ ID NO: 943, SEQID NO: 949, SEQ ID NO: 955, SEQ ID NO: 961, SEQ ID NO: 967, SEQ ID NO:973, SEQ ID NO: 979, SEQ ID NO: 985, SEQ ID NO: 991, SEQ ID NO: 997, SEQID NO: 1003, SEQ ID NO: 1009, SEQ ID NO: 1015, SEQ ID NO: 1021, SEQ IDNO: 1027, SEQ ID NO: 1033, SEQ ID NO: 1039, SEQ ID NO: 1045, SEQ ID NO:1051, SEQ ID NO: 1057, SEQ ID NO: 1063, SEQ ID NO: 1069, SEQ ID NO:1075, SEQ ID NO: 1081, SEQ ID NO: 1087, SEQ ID NO: 1093, SEQ ID NO:1099, SEQ ID NO: 1105, SEQ ID NO: 1111, SEQ ID NO: 1117, SEQ ID NO:1123, SEQ ID NO: 1129, SEQ ID NO: 1135, SEQ ID NO: 1141, SEQ ID NO:1147, SEQ ID NO: 1153, SEQ ID NO: 1159, SEQ ID NO: 1165, SEQ ID NO:1171, SEQ ID NO: 1177, SEQ ID NO: 1183, SEQ ID NO: 1189, SEQ ID NO:1195, SEQ ID NO: 1201, SEQ ID NO: 1207, SEQ ID NO: 1213, SEQ ID NO:1219, SEQ ID NO: 1225, SEQ ID NO: 1231, SEQ ID NO: 1237, SEQ ID NO:1243, SEQ ID NO: 1249, SEQ ID NO: 1255, SEQ ID NO: 1261, SEQ ID NO:1267, SEQ ID NO: 1273, SEQ ID NO: 1279, SEQ ID NO: 1285, SEQ ID NO:1291, SEQ ID NO: 1297, SEQ ID NO: 1303, SEQ ID NO: 1309, SEQ ID NO:1315, SEQ ID NO: 1321, SEQ ID NO: 1327, SEQ ID NO: 1333, SEQ ID NO:1339, SEQ ID NO: 1345, SEQ ID NO: 1351, SEQ ID NO: 1357, SEQ ID NO:1363, SEQ ID NO: 1369, SEQ ID NO: 1375, SEQ ID NO: 1381, SEQ ID NO:1387, SEQ ID NO: 1393, SEQ ID NO: 1399, SEQ ID NO: 1405, SEQ ID NO:1411, SEQ ID NO: 1417, SEQ ID NO: 1423, SEQ ID NO: 1429, SEQ ID NO:1435, SEQ ID NO: 1441, SEQ ID NO: 1447, SEQ ID NO: 1453, SEQ ID NO:1459, SEQ ID NO: 1465, SEQ ID NO: 1471, SEQ ID NO: 1477, SEQ ID NO:1483, SEQ ID NO: 1489, SEQ ID NO: 1495, SEQ ID NO: 1501, SEQ ID NO:1507, SEQ ID NO: 1513, SEQ ID NO: 1519, SEQ ID NO: 1593, SEQ ID NO: 1525SEQ ID NO: 1531, SEQ ID NO: 1537, SEQ ID NO: 1543, SEQ ID NO: 1549, SEQID NO: 1555, SEQ ID NO: 1561, SEQ ID NO: 1567, SEQ ID NO: 1573, SEQ IDNO: 1579, or SEQ ID NO: 1585 as shown in FIG. 3A, 3B, 3C, 3D, 3E, 3F,3G, 3H, 3I, 3J, 3K, or 3L, a heavy chain CDR2 comprising the amino acidsequence of any one of the HCDR2s in SEQ ID NO: 398, SEQ ID NO: 404, SEQID NO: 410, SEQ ID NO: 416, SEQ ID NO: 422, SEQ ID NO: 428, SEQ ID NO:434, SEQ ID NO: 440, SEQ ID NO: 446, SEQ ID NO: 452, SEQ ID NO: 458, SEQID NO: 464, SEQ ID NO: 470, SEQ ID NO: 476, SEQ ID NO: 482, SEQ ID NO:488, SEQ ID NO: 494, SEQ ID NO: 500, SEQ ID NO: 506, SEQ ID NO: 512, SEQID NO: 518, SEQ ID NO: 524, SEQ ID NO: 530, SEQ ID NO: 536, SEQ ID NO:542, SEQ ID NO: 548, SEQ ID NO: 554, SEQ ID NO: 560, SEQ ID NO: 566, SEQID NO: 572, SEQ ID NO: 578, SEQ ID NO: 584, SEQ ID NO: 590, SEQ ID NO:596, SEQ ID NO: 602, SEQ ID NO: 608, SEQ ID NO: 614, SEQ ID NO: 620, SEQID NO: 626, SEQ ID NO: 632, SEQ ID NO: 638, SEQ ID NO: 644, SEQ ID NO:650, SEQ ID NO: 656, SEQ ID NO: 662, SEQ ID NO: 668, SEQ ID NO: 674, SEQID NO: 680, SEQ ID NO: 686, SEQ ID NO: 692, SEQ ID NO: 698, SEQ ID NO:704, SEQ ID NO: 710, SEQ ID NO: 716, SEQ ID NO: 722, SEQ ID NO: 728, SEQID NO: 734, SEQ ID NO: 740, SEQ ID NO: 746, SEQ ID NO: 752, SEQ ID NO:758, SEQ ID NO: 764, SEQ ID NO: 770, SEQ ID NO: 776, SEQ ID NO: 782, SEQID NO: 788, SEQ ID NO: 794, SEQ ID NO: 800, SEQ ID NO: 806, SEQ ID NO:812, SEQ ID NO: 818, SEQ ID NO: 824, SEQ ID NO: 830, SEQ ID NO: 836, SEQID NO: 842, SEQ ID NO: 848, SEQ ID NO: 854, SEQ ID NO: 860, SEQ ID NO:866, SEQ ID NO: 872, SEQ ID NO: 878, SEQ ID NO: 884, SEQ ID NO: 890, SEQID NO: 896, SEQ ID NO: 902, SEQ ID NO: 908, SEQ ID NO: 914, SEQ ID NO:920, SEQ ID NO: 926, SEQ ID NO: 932, SEQ ID NO: 938, SEQ ID NO: 944, SEQID NO: 950, SEQ ID NO: 956, SEQ ID NO: 962, SEQ ID NO: 968, SEQ ID NO:974, SEQ ID NO: 980, SEQ ID NO: 986, SEQ ID NO: 992, SEQ ID NO: 998, SEQID NO: 1004, SEQ ID NO: 1010, SEQ ID NO: 1016, SEQ ID NO: 1022, SEQ IDNO: 1028, SEQ ID NO: 1034, SEQ ID NO: 1040, SEQ ID NO: 1046, SEQ ID NO:1052, SEQ ID NO: 1058, SEQ ID NO: 1064, SEQ ID NO: 1070, SEQ ID NO:1076, SEQ ID NO: 1082, SEQ ID NO: 1088, SEQ ID NO: 1094, SEQ ID NO:1100, SEQ ID NO: 1106, SEQ ID NO: 1112, SEQ ID NO: 1118, SEQ ID NO:1124, SEQ ID NO: 1130, SEQ ID NO: 1136, SEQ ID NO: 1142, SEQ ID NO:1148, SEQ ID NO: 1154, SEQ ID NO: 1160, SEQ ID NO: 1166, SEQ ID NO:1172, SEQ ID NO: 1178, SEQ ID NO: 1184, SEQ ID NO: 1190, SEQ ID NO:1196, SEQ ID NO: 1202, SEQ ID NO: 1208, SEQ ID NO: 1214, SEQ ID NO:1220, SEQ ID NO: 1226, SEQ ID NO: 1232, SEQ ID NO: 1238, SEQ ID NO:1244, SEQ ID NO: 1250, SEQ ID NO: 1256, SEQ ID NO: 1262, SEQ ID NO:1268, SEQ ID NO: 1274, SEQ ID NO: 1280, SEQ ID NO: 1286, SEQ ID NO:1292, SEQ ID NO: 1298, SEQ ID NO: 1304, SEQ ID NO: 1310, SEQ ID NO:1316, SEQ ID NO: 1322, SEQ ID NO: 1328, SEQ ID NO: 1334, SEQ ID NO:1340, SEQ ID NO: 1346, SEQ ID NO: 1352, SEQ ID NO: 1358, SEQ ID NO:1364, SEQ ID NO: 1370, SEQ ID NO: 1376, SEQ ID NO: 1382, SEQ ID NO:1388, SEQ ID NO: 1394, SEQ ID NO: 1400, SEQ ID NO: 1406, SEQ ID NO:1412, SEQ ID NO: 1418, SEQ ID NO: 1424, SEQ ID NO: 1430, SEQ ID NO:1436, SEQ ID NO: 1442, SEQ ID NO: 1448, SEQ ID NO: 1454, SEQ ID NO:1460, SEQ ID NO: 1466, SEQ ID NO: 1472, SEQ ID NO: 1478, SEQ ID NO:1484, SEQ ID NO: 1490, SEQ ID NO: 1496, SEQ ID NO: 1502, SEQ ID NO:1508, SEQ ID NO: 1514, SEQ ID NO: 1520, SEQ ID NO: 1594, SEQ ID NO:1526, SEQ ID NO: 1532, SEQ ID NO: 1538, SEQ ID NO: 1544, SEQ ID NO:1550, SEQ ID NO: 1556, SEQ ID NO: 1562, SEQ ID NO: 1568, SEQ ID NO:1574, SEQ ID NO: 1580, or SEQ ID NO: 1586 as shown in in FIG. 3A, 3B,3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, and a heavy chain CDR3comprising the amino acid sequence of any one of the HCDR3s in SEQ IDNO: 399, SEQ ID NO: 405, SEQ ID NO: 411, SEQ ID NO: 417, SEQ ID NO: 423,SEQ ID NO: 429, SEQ ID NO: 435, SEQ ID NO: 441, SEQ ID NO: 447, SEQ IDNO: 453, SEQ ID NO: 459, SEQ ID NO: 465, SEQ ID NO: 471, SEQ ID NO: 477,SEQ ID NO: 483, SEQ ID NO: 489, SEQ ID NO: 495, SEQ ID NO: 501, SEQ IDNO: 507, SEQ ID NO: 513, SEQ ID NO: 519, SEQ ID NO: 525, SEQ ID NO: 531,SEQ ID NO: 537, SEQ ID NO: 543, SEQ ID NO: 549, SEQ ID NO: 555, SEQ IDNO: 561, SEQ ID NO: 567, SEQ ID NO: 573, SEQ ID NO: 579, SEQ ID NO: 585,SEQ ID NO: 591, SEQ ID NO: 597, SEQ ID NO: 603, SEQ ID NO: 609, SEQ IDNO: 615, SEQ ID NO: 621, SEQ ID NO: 627, SEQ ID NO: 633, SEQ ID NO: 639,SEQ ID NO: 645, SEQ ID NO: 651, SEQ ID NO: 657, SEQ ID NO: 663, SEQ IDNO: 669, SEQ ID NO: 675, SEQ ID NO: 681, SEQ ID NO: 687, SEQ ID NO: 693,SEQ ID NO: 699, SEQ ID NO: 705, SEQ ID NO: 711, SEQ ID NO: 717, SEQ IDNO: 723, SEQ ID NO: 729, SEQ ID NO: 735, SEQ ID NO: 741, SEQ ID NO: 747,SEQ ID NO: 753, SEQ ID NO: 759, SEQ ID NO: 765, SEQ ID NO: 771, SEQ IDNO: 777, SEQ ID NO: 783, SEQ ID NO: 789, SEQ ID NO: 795, SEQ ID NO: 801,SEQ ID NO: 807, SEQ ID NO: 813, SEQ ID NO: 819, SEQ ID NO: 825, SEQ IDNO: 831, SEQ ID NO: 837, SEQ ID NO: 843, SEQ ID NO: 849, SEQ ID NO: 855,SEQ ID NO: 861, SEQ ID NO: 867, SEQ ID NO: 873, SEQ ID NO: 879, SEQ IDNO: 885, SEQ ID NO: 891, SEQ ID NO: 897, SEQ ID NO: 903, SEQ ID NO: 909,SEQ ID NO: 915, SEQ ID NO: 921, SEQ ID NO: 927, SEQ ID NO: 933, SEQ IDNO: 939, SEQ ID NO: 945, SEQ ID NO: 951, SEQ ID NO: 957, SEQ ID NO: 963,SEQ ID NO: 969, SEQ ID NO: 975, SEQ ID NO: 981, SEQ ID NO: 987, SEQ IDNO: 993, SEQ ID NO: 999, SEQ ID NO: 1005, SEQ ID NO: 1011, SEQ ID NO:1017, SEQ ID NO: 1023, SEQ ID NO: 1029, SEQ ID NO: 1035, SEQ ID NO:1041, SEQ ID NO: 1047, SEQ ID NO: 1053, SEQ ID NO: 1059, SEQ ID NO:1065, SEQ ID NO: 1071, SEQ ID NO: 1077, SEQ ID NO: 1083, SEQ ID NO:1089, SEQ ID NO: 1095, SEQ ID NO: 1101, SEQ ID NO: 1107, SEQ ID NO:1113, SEQ ID NO: 1119, SEQ ID NO: 1125, SEQ ID NO: 1131, SEQ ID NO:1137, SEQ ID NO: 1143, SEQ ID NO: 1149, SEQ ID NO: 1155, SEQ ID NO:1161, SEQ ID NO: 1167, SEQ ID NO: 1173, SEQ ID NO: 1179, SEQ ID NO:1185, SEQ ID NO: 1191, SEQ ID NO: 1197, SEQ ID NO: 1203, SEQ ID NO:1209, SEQ ID NO: 1215, SEQ ID NO: 1221, SEQ ID NO: 1227, SEQ ID NO:1233, SEQ ID NO: 1239, SEQ ID NO: 1245, SEQ ID NO: 1251, SEQ ID NO:1257, SEQ ID NO: 1263, SEQ ID NO: 1269, SEQ ID NO: 1275, SEQ ID NO:1281, SEQ ID NO: 1287, SEQ ID NO: 1293, SEQ ID NO: 1299, SEQ ID NO:1305, SEQ ID NO: 1311, SEQ ID NO: 1317, SEQ ID NO: 1323, SEQ ID NO:1329, SEQ ID NO: 1335, SEQ ID NO: 1341, SEQ ID NO: 1347, SEQ ID NO:1353, SEQ ID NO: 1359, SEQ ID NO: 1365, SEQ ID NO: 1371, SEQ ID NO:1377, SEQ ID NO: 1383, SEQ ID NO: 1389, SEQ ID NO: 1395, SEQ ID NO:1401, SEQ ID NO: 1407, SEQ ID NO: 1413, SEQ ID NO: 1419, SEQ ID NO:1425, SEQ ID NO: 1431, SEQ ID NO: 1437, SEQ ID NO: 1443, SEQ ID NO:1449, SEQ ID NO: 1455, SEQ ID NO: 1461, SEQ ID NO: 1467, SEQ ID NO:1473, SEQ ID NO: 1479, SEQ ID NO: 1485, SEQ ID NO: 1491, SEQ ID NO:1497, SEQ ID NO: 1503, SEQ ID NO: 1509, SEQ ID NO: 1515, SEQ ID NO:1521, SEQ ID NO: 1595, SEQ ID NO: 1527, SEQ ID NO: 1533, SEQ ID NO:1539, SEQ ID NO: 1545, SEQ ID NO: 1551, SEQ ID NO: 1557, SEQ ID NO:1563, SEQ ID NO: 1569, SEQ ID NO: 1575, SEQ ID NO: 1581, or SEQ ID NO:1587 as shown in in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or3L, and the HCDR1, HCDR2, and HCDR3 are from a same clone

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain CDR1 comprising the amino acidsequence of any of one of the HCDR1s in SEQ ID NO: 397, SEQ ID NO: 403.SEQ ID NO: 409, SEQ ID NO: 415, SEQ ID NO: 421, SEQ ID NO: 427, SEQ IDNO: 433, SEQ ID NO: 439, SEQ ID NO: 445, SEQ ID NO: 451, SEQ ID NO: 457,SEQ ID NO: 463, SEQ ID NO: 469, SEQ ID NO: 475, SEQ ID NO: 481, SEQ IDNO: 487, SEQ ID NO: 493, SEQ ID NO: 499, SEQ ID NO: 505, SEQ ID NO: 511,SEQ ID NO: 517, SEQ ID NO: 523, SEQ ID NO: 529, SEQ ID NO: 535, SEQ IDNO: 541, SEQ ID NO: 547, SEQ ID NO: 553, SEQ ID NO: 559, SEQ ID NO: 565,SEQ ID NO: 571, SEQ ID NO: 577, SEQ ID NO: 583, SEQ ID NO: 589, SEQ IDNO: 595, SEQ ID NO: 601, SEQ ID NO: 607, SEQ ID NO: 613, SEQ ID NO: 619,SEQ ID NO: 625, SEQ ID NO: 631, SEQ ID NO: 637, SEQ ID NO: 643, SEQ IDNO: 649, SEQ ID NO: 655, SEQ ID NO: 661, SEQ ID NO: 667, SEQ ID NO: 673,SEQ ID NO: 679, SEQ ID NO: 685, SEQ ID NO: 691, SEQ ID NO: 697, SEQ IDNO: 703, SEQ ID NO: 709, SEQ ID NO: 715, SEQ ID NO: 721, SEQ ID NO: 727,SEQ ID NO: 733, SEQ ID NO: 739, SEQ ID NO: 745, SEQ ID NO: 751, SEQ IDNO: 757, SEQ ID NO: 763, SEQ ID NO: 769, SEQ ID NO: 775, SEQ ID NO: 781,SEQ ID NO: 787, SEQ ID NO: 793, SEQ ID NO: 799, SEQ ID NO: 805, SEQ IDNO: 811, SEQ ID NO: 817, SEQ ID NO: 823, SEQ ID NO: 829, SEQ ID NO: 835,SEQ ID NO: 841, SEQ ID NO: 847, SEQ ID NO: 853, SEQ ID NO: 859, SEQ IDNO: 865, SEQ ID NO: 871, SEQ ID NO: 877, SEQ ID NO: 883, SEQ ID NO: 889,SEQ ID NO: 895, SEQ ID NO: 901, SEQ ID NO: 907, SEQ ID NO: 913, SEQ IDNO: 919, SEQ ID NO: 925, SEQ ID NO: 931, SEQ ID NO: 937, SEQ ID NO: 943,SEQ ID NO: 949, SEQ ID NO: 955, SEQ ID NO: 961, SEQ ID NO: 967, SEQ IDNO: 973, SEQ ID NO: 979, SEQ ID NO: 985, SEQ ID NO: 991, SEQ ID NO: 997,SEQ ID NO: 1003, SEQ ID NO: 1009, SEQ ID NO: 1015, SEQ ID NO: 1021, SEQID NO: 1027, SEQ ID NO: 1033, SEQ ID NO: 1039, SEQ ID NO: 1045, SEQ IDNO: 1051, SEQ ID NO: 1057, SEQ ID NO: 1063, SEQ ID NO: 1069, SEQ ID NO:1075, SEQ ID NO: 1081, SEQ ID NO: 1087, SEQ ID NO: 1093, SEQ ID NO:1099, SEQ ID NO: 1105, SEQ ID NO: 1111, SEQ ID NO: 1117, SEQ ID NO:1123, SEQ ID NO: 1129, SEQ ID NO: 1135, SEQ ID NO: 1141, SEQ ID NO:1147, SEQ ID NO: 1153, SEQ ID NO: 1159, SEQ ID NO: 1165, SEQ ID NO:1171, SEQ ID NO: 1177, SEQ ID NO: 1183, SEQ ID NO: 1189, SEQ ID NO:1195, SEQ ID NO: 1201, SEQ ID NO: 1207, SEQ ID NO: 1213, SEQ ID NO:1219, SEQ ID NO: 1225, SEQ ID NO: 1231, SEQ ID NO: 1237, SEQ ID NO:1243, SEQ ID NO: 1249, SEQ ID NO: 1255, SEQ ID NO: 1261, SEQ ID NO:1267, SEQ ID NO: 1273, SEQ ID NO: 1279, SEQ ID NO: 1285, SEQ ID NO:1291, SEQ ID NO: 1297, SEQ ID NO: 1303, SEQ ID NO: 1309, SEQ ID NO:1315, SEQ ID NO: 1321, SEQ ID NO: 1327, SEQ ID NO: 1333, SEQ ID NO:1339, SEQ ID NO: 1345, SEQ ID NO: 1351, SEQ ID NO: 1357, SEQ ID NO:1363, SEQ ID NO: 1369, SEQ ID NO: 1375, SEQ ID NO: 1381, SEQ ID NO:1387, SEQ ID NO: 1393, SEQ ID NO: 1399, SEQ ID NO: 1405, SEQ ID NO:1411, SEQ ID NO: 1417, SEQ ID NO: 1423, SEQ ID NO: 1429, SEQ ID NO:1435, SEQ ID NO: 1441, SEQ ID NO: 1447, SEQ ID NO: 1453, SEQ ID NO:1459, SEQ ID NO: 1465, SEQ ID NO: 1471, SEQ ID NO: 1477, SEQ ID NO:1483, SEQ ID NO: 1489, SEQ ID NO: 1495, SEQ ID NO: 1501, SEQ ID NO:1507, SEQ ID NO: 1513, SEQ ID NO: 1519, SEQ ID NO: 1593, SEQ ID NO: 1525SEQ ID NO: 1531, SEQ ID NO: 1537, SEQ ID NO: 1543, SEQ ID NO: 1549, SEQID NO: 1555, SEQ ID NO: 1561, SEQ ID NO: 1567, SEQ ID NO: 1573, SEQ IDNO: 1579, or SEQ ID NO: 1585 as shown in FIG. 3A, 3B, 3C, 3D, 3E, 3F,3G, 3H, 3I, 3J, 3K, or 3L, a heavy chain CDR2 comprising the amino acidsequence of any one of the HCDR2s in SEQ ID NO: 398, SEQ ID NO: 404, SEQID NO: 410, SEQ ID NO: 416, SEQ ID NO: 422, SEQ ID NO: 428, SEQ ID NO:434, SEQ ID NO: 440, SEQ ID NO: 446, SEQ ID NO: 452, SEQ ID NO: 458, SEQID NO: 464, SEQ ID NO: 470, SEQ ID NO: 476, SEQ ID NO: 482, SEQ ID NO:488, SEQ ID NO: 494, SEQ ID NO: 500, SEQ ID NO: 506, SEQ ID NO: 512, SEQID NO: 518, SEQ ID NO: 524, SEQ ID NO: 530, SEQ ID NO: 536, SEQ ID NO:542, SEQ ID NO: 548, SEQ ID NO: 554, SEQ ID NO: 560, SEQ ID NO: 566, SEQID NO: 572, SEQ ID NO: 578, SEQ ID NO: 584, SEQ ID NO: 590, SEQ ID NO:596, SEQ ID NO: 602, SEQ ID NO: 608, SEQ ID NO: 614, SEQ ID NO: 620, SEQID NO: 626, SEQ ID NO: 632, SEQ ID NO: 638, SEQ ID NO: 644, SEQ ID NO:650, SEQ ID NO: 656, SEQ ID NO: 662, SEQ ID NO: 668, SEQ ID NO: 674, SEQID NO: 680, SEQ ID NO: 686, SEQ ID NO: 692, SEQ ID NO: 698, SEQ ID NO:704, SEQ ID NO: 710, SEQ ID NO: 716, SEQ ID NO: 722, SEQ ID NO: 728, SEQID NO: 734, SEQ ID NO: 740, SEQ ID NO: 746, SEQ ID NO: 752, SEQ ID NO:758, SEQ ID NO: 764, SEQ ID NO: 770, SEQ ID NO: 776, SEQ ID NO: 782, SEQID NO: 788, SEQ ID NO: 794, SEQ ID NO: 800, SEQ ID NO: 806, SEQ ID NO:812, SEQ ID NO: 818, SEQ ID NO: 824, SEQ ID NO: 830, SEQ ID NO: 836, SEQID NO: 842, SEQ ID NO: 848, SEQ ID NO: 854, SEQ ID NO: 860, SEQ ID NO:866, SEQ ID NO: 872, SEQ ID NO: 878, SEQ ID NO: 884, SEQ ID NO: 890, SEQID NO: 896, SEQ ID NO: 902, SEQ ID NO: 908, SEQ ID NO: 914, SEQ ID NO:920, SEQ ID NO: 926, SEQ ID NO: 932, SEQ ID NO: 938, SEQ ID NO: 944, SEQID NO: 950, SEQ ID NO: 956, SEQ ID NO: 962, SEQ ID NO: 968, SEQ ID NO:974, SEQ ID NO: 980, SEQ ID NO: 986, SEQ ID NO: 992, SEQ ID NO: 998, SEQID NO: 1004, SEQ ID NO: 1010, SEQ ID NO: 1016, SEQ ID NO: 1022, SEQ IDNO: 1028, SEQ ID NO: 1034, SEQ ID NO: 1040, SEQ ID NO: 1046, SEQ ID NO:1052, SEQ ID NO: 1058, SEQ ID NO: 1064, SEQ ID NO: 1070, SEQ ID NO:1076, SEQ ID NO: 1082, SEQ ID NO: 1088, SEQ ID NO: 1094, SEQ ID NO:1100, SEQ ID NO: 1106, SEQ ID NO: 1112, SEQ ID NO: 1118, SEQ ID NO:1124, SEQ ID NO: 1130, SEQ ID NO: 1136, SEQ ID NO: 1142, SEQ ID NO:1148, SEQ ID NO: 1154, SEQ ID NO: 1160, SEQ ID NO: 1166, SEQ ID NO:1172, SEQ ID NO: 1178, SEQ ID NO: 1184, SEQ ID NO: 1190, SEQ ID NO:1196, SEQ ID NO: 1202, SEQ ID NO: 1208, SEQ ID NO: 1214, SEQ ID NO:1220, SEQ ID NO: 1226, SEQ ID NO: 1232, SEQ ID NO: 1238, SEQ ID NO:1244, SEQ ID NO: 1250, SEQ ID NO: 1256, SEQ ID NO: 1262, SEQ ID NO:1268, SEQ ID NO: 1274, SEQ ID NO: 1280, SEQ ID NO: 1286, SEQ ID NO:1292, SEQ ID NO: 1298, SEQ ID NO: 1304, SEQ ID NO: 1310, SEQ ID NO:1316, SEQ ID NO: 1322, SEQ ID NO: 1328, SEQ ID NO: 1334, SEQ ID NO:1340, SEQ ID NO: 1346, SEQ ID NO: 1352, SEQ ID NO: 1358, SEQ ID NO:1364, SEQ ID NO: 1370, SEQ ID NO: 1376, SEQ ID NO: 1382, SEQ ID NO:1388, SEQ ID NO: 1394, SEQ ID NO: 1400, SEQ ID NO: 1406, SEQ ID NO:1412, SEQ ID NO: 1418, SEQ ID NO: 1424, SEQ ID NO: 1430, SEQ ID NO:1436, SEQ ID NO: 1442, SEQ ID NO: 1448, SEQ ID NO: 1454, SEQ ID NO:1460, SEQ ID NO: 1466, SEQ ID NO: 1472, SEQ ID NO: 1478, SEQ ID NO:1484, SEQ ID NO: 1490, SEQ ID NO: 1496, SEQ ID NO: 1502, SEQ ID NO:1508, SEQ ID NO: 1514, SEQ ID NO: 1520, SEQ ID NO: 1594, SEQ ID NO:1526, SEQ ID NO: 1532, SEQ ID NO: 1538, SEQ ID NO: 1544, SEQ ID NO:1550, SEQ ID NO: 1556, SEQ ID NO: 1562, SEQ ID NO: 1568, SEQ ID NO:1574, SEQ ID NO: 1580, or SEQ ID NO: 1586 as shown in FIG. 3A, 3B, 3C,3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, a heavy chain CDR3 comprising theamino acid sequence of any one of the HCDR3s in SEQ ID NO: 399, SEQ IDNO: 405, SEQ ID NO: 411, SEQ ID NO: 417, SEQ ID NO: 423, SEQ ID NO: 429,SEQ ID NO: 435, SEQ ID NO: 441, SEQ ID NO: 447, SEQ ID NO: 453, SEQ IDNO: 459, SEQ ID NO: 465, SEQ ID NO: 471, SEQ ID NO: 477, SEQ ID NO: 483,SEQ ID NO: 489, SEQ ID NO: 495, SEQ ID NO: 501, SEQ ID NO: 507, SEQ IDNO: 513, SEQ ID NO: 519, SEQ ID NO: 525, SEQ ID NO: 531, SEQ ID NO: 537,SEQ ID NO: 543, SEQ ID NO: 549, SEQ ID NO: 555, SEQ ID NO: 561, SEQ IDNO: 567, SEQ ID NO: 573, SEQ ID NO: 579, SEQ ID NO: 585, SEQ ID NO: 591,SEQ ID NO: 597, SEQ ID NO: 603, SEQ ID NO: 609, SEQ ID NO: 615, SEQ IDNO: 621, SEQ ID NO: 627, SEQ ID NO: 633, SEQ ID NO: 639, SEQ ID NO: 645,SEQ ID NO: 651, SEQ ID NO: 657, SEQ ID NO: 663, SEQ ID NO: 669, SEQ IDNO: 675, SEQ ID NO: 681, SEQ ID NO: 687, SEQ ID NO: 693, SEQ ID NO: 699,SEQ ID NO: 705, SEQ ID NO: 711, SEQ ID NO: 717, SEQ ID NO: 723, SEQ IDNO: 729, SEQ ID NO: 735, SEQ ID NO: 741, SEQ ID NO: 747, SEQ ID NO: 753,SEQ ID NO: 759, SEQ ID NO: 765, SEQ ID NO: 771, SEQ ID NO: 777, SEQ IDNO: 783, SEQ ID NO: 789, SEQ ID NO: 795, SEQ ID NO: 801, SEQ ID NO: 807,SEQ ID NO: 813, SEQ ID NO: 819, SEQ ID NO: 825, SEQ ID NO: 831, SEQ IDNO: 837, SEQ ID NO: 843, SEQ ID NO: 849, SEQ ID NO: 855, SEQ ID NO: 861,SEQ ID NO: 867, SEQ ID NO: 873, SEQ ID NO: 879, SEQ ID NO: 885, SEQ IDNO: 891, SEQ ID NO: 897, SEQ ID NO: 903, SEQ ID NO: 909, SEQ ID NO: 915,SEQ ID NO: 921, SEQ ID NO: 927, SEQ ID NO: 933, SEQ ID NO: 939, SEQ IDNO: 945, SEQ ID NO: 951, SEQ ID NO: 957, SEQ ID NO: 963, SEQ ID NO: 969,SEQ ID NO: 975, SEQ ID NO: 981, SEQ ID NO: 987, SEQ ID NO: 993, SEQ IDNO: 999, SEQ ID NO: 1005, SEQ ID NO: 1011, SEQ ID NO: 1017, SEQ ID NO:1023, SEQ ID NO: 1029, SEQ ID NO: 1035, SEQ ID NO: 1041, SEQ ID NO:1047, SEQ ID NO: 1053, SEQ ID NO: 1059, SEQ ID NO: 1065, SEQ ID NO:1071, SEQ ID NO: 1077, SEQ ID NO: 1083, SEQ ID NO: 1089, SEQ ID NO:1095, SEQ ID NO: 1101, SEQ ID NO: 1107, SEQ ID NO: 1113, SEQ ID NO:1119, SEQ ID NO: 1125, SEQ ID NO: 1131, SEQ ID NO: 1137, SEQ ID NO:1143, SEQ ID NO: 1149, SEQ ID NO: 1155, SEQ ID NO: 1161, SEQ ID NO:1167, SEQ ID NO: 1173, SEQ ID NO: 1179, SEQ ID NO: 1185, SEQ ID NO:1191, SEQ ID NO: 1197, SEQ ID NO: 1203, SEQ ID NO: 1209, SEQ ID NO:1215, SEQ ID NO: 1221, SEQ ID NO: 1227, SEQ ID NO: 1233, SEQ ID NO:1239, SEQ ID NO: 1245, SEQ ID NO: 1251, SEQ ID NO: 1257, SEQ ID NO:1263, SEQ ID NO: 1269, SEQ ID NO: 1275, SEQ ID NO: 1281, SEQ ID NO:1287, SEQ ID NO: 1293, SEQ ID NO: 1299, SEQ ID NO: 1305, SEQ ID NO:1311, SEQ ID NO: 1317, SEQ ID NO: 1323, SEQ ID NO: 1329, SEQ ID NO:1335, SEQ ID NO: 1341, SEQ ID NO: 1347, SEQ ID NO: 1353, SEQ ID NO:1359, SEQ ID NO: 1365, SEQ ID NO: 1371, SEQ ID NO: 1377, SEQ ID NO:1383, SEQ ID NO: 1389, SEQ ID NO: 1395, SEQ ID NO: 1401, SEQ ID NO:1407, SEQ ID NO: 1413, SEQ ID NO: 1419, SEQ ID NO: 1425, SEQ ID NO:1431, SEQ ID NO: 1437, SEQ ID NO: 1443, SEQ ID NO: 1449, SEQ ID NO:1455, SEQ ID NO: 1461, SEQ ID NO: 1467, SEQ ID NO: 1473, SEQ ID NO:1479, SEQ ID NO: 1485, SEQ ID NO: 1491, SEQ ID NO: 1497, SEQ ID NO:1503, SEQ ID NO: 1509, SEQ ID NO: 1515, SEQ ID NO: 1521, SEQ ID NO:1595, SEQ ID NO: 1527, SEQ ID NO: 1533, SEQ ID NO: 1539, SEQ ID NO:1545, SEQ ID NO: 1551, SEQ ID NO: 1557, SEQ ID NO: 1563, SEQ ID NO:1569, SEQ ID NO: 1575, SEQ ID NO: 1581, or SEQ ID NO: 1587 as shown inin FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, a light chainCDR1 comprising the amino acid sequence of any one of the LCDR1s in SEQID NO: 400, SEQ ID NO: 406, SEQ ID NO: 412, SEQ ID NO: 418, SEQ ID NO:424, SEQ ID NO: 430, SEQ ID NO: 436, SEQ ID NO: 442, SEQ ID NO: 448, SEQID NO: 454, SEQ ID NO: 460, SEQ ID NO: 466, SEQ ID NO: 472, SEQ ID NO:478, SEQ ID NO: 484, SEQ ID NO: 490, SEQ ID NO: 496, SEQ ID NO: 502, SEQID NO: 508, SEQ ID NO: 514, SEQ ID NO: 520, SEQ ID NO: 526, SEQ ID NO:532, SEQ ID NO: 538, SEQ ID NO: 544, SEQ ID NO: 550, SEQ ID NO: 556, SEQID NO: 562, SEQ ID NO: 568, SEQ ID NO: 574, SEQ ID NO: 580, SEQ ID NO:586, SEQ ID NO: 592, SEQ ID NO: 598, SEQ ID NO: 604, SEQ ID NO: 610, SEQID NO: 616, SEQ ID NO: 622, SEQ ID NO: 628, SEQ ID NO: 634, SEQ ID NO:640, SEQ ID NO: 646, SEQ ID NO: 652, SEQ ID NO: 658, SEQ ID NO: 664, SEQID NO: 670, SEQ ID NO: 676, SEQ ID NO: 682, SEQ ID NO: 688, SEQ ID NO:694, SEQ ID NO: 700, SEQ ID NO: 706, SEQ ID NO: 712, SEQ ID NO: 718, SEQID NO: 724, SEQ ID NO: 730, SEQ ID NO: 736, SEQ ID NO: 742, SEQ ID NO:748, SEQ ID NO: 754, SEQ ID NO: 760, SEQ ID NO: 766, SEQ ID NO: 772, SEQID NO: 778, SEQ ID NO: 784, SEQ ID NO: 790, SEQ ID NO: 796, SEQ ID NO:802, SEQ ID NO: 808, SEQ ID NO: 814, SEQ ID NO: 820, SEQ ID NO: 826, SEQID NO: 832, SEQ ID NO: 838, SEQ ID NO: 844, SEQ ID NO: 850, SEQ ID NO:856, SEQ ID NO: 862, SEQ ID NO: 868, SEQ ID NO: 874, SEQ ID NO: 880, SEQID NO: 886, SEQ ID NO: 892, SEQ ID NO: 898, SEQ ID NO: 904, SEQ ID NO:910, SEQ ID NO: 916, SEQ ID NO: 922, SEQ ID NO: 928, SEQ ID NO: 934, SEQID NO: 940, SEQ ID NO: 946, SEQ ID NO: 952, SEQ ID NO: 958, SEQ ID NO:964, SEQ ID NO: 970, SEQ ID NO: 976, SEQ ID NO: 982, SEQ ID NO: 988, SEQID NO: 994, SEQ ID NO: 1000, SEQ ID NO: 1006, SEQ ID NO: 1012, SEQ IDNO: 1018, SEQ ID NO: 1024, SEQ ID NO: 1030, SEQ ID NO: 1036, SEQ ID NO:1042, SEQ ID NO: 1048, SEQ ID NO: 1054, SEQ ID NO: 1060, SEQ ID NO:1066, SEQ ID NO: 1072, SEQ ID NO: 1078, SEQ ID NO: 1084, SEQ ID NO:1090, SEQ ID NO: 1096, SEQ ID NO: 1102, SEQ ID NO: 1108, SEQ ID NO:1114, SEQ ID NO: 1120, SEQ ID NO: 1126, SEQ ID NO: 1132, SEQ ID NO:1138, SEQ ID NO: 1144, SEQ ID NO: 1150, SEQ ID NO: 1156, SEQ ID NO:1162, SEQ ID NO: 1168, SEQ ID NO: 1174, SEQ ID NO: 1180, SEQ ID NO:1186, SEQ ID NO: 1192, SEQ ID NO: 1198, SEQ ID NO: 1204, SEQ ID NO:1210, SEQ ID NO: 1216, SEQ ID NO: 1222, SEQ ID NO: 1228, SEQ ID NO:1234, SEQ ID NO: 1240, SEQ ID NO: 1246, SEQ ID NO: 1252, SEQ ID NO:1258, SEQ ID NO: 1264, SEQ ID NO: 1270, SEQ ID NO: 1276, SEQ ID NO:1282, SEQ ID NO: 1288, SEQ ID NO: 1294, SEQ ID NO: 1300, SEQ ID NO:1306, SEQ ID NO: 1312, SEQ ID NO: 1318, SEQ ID NO: 1324, SEQ ID NO:1330, SEQ ID NO: 1336, SEQ ID NO: 1342, SEQ ID NO: 1348, SEQ ID NO:1354, SEQ ID NO: 1360, SEQ ID NO: 1366, SEQ ID NO: 1372, SEQ ID NO:1378, SEQ ID NO: 1384, SEQ ID NO: 1390, SEQ ID NO: 1396, SEQ ID NO:1402, SEQ ID NO: 1408, SEQ ID NO: 1414, SEQ ID NO: 1420, SEQ ID NO:1426, SEQ ID NO: 1432, SEQ ID NO: 1438, SEQ ID NO: 1444, SEQ ID NO:1450. SEQ ID NO: 1456, SEQ ID NO: 1462, SEQ ID NO: 1468, SEQ ID NO:1474, SEQ ID NO: 1480, SEQ ID NO: 1486, SEQ ID NO: 1492, SEQ ID NO:1498, SEQ ID NO: 1504, SEQ ID NO: 1510, SEQ ID NO: 1516, SEQ ID NO:1522, SEQ ID NO: 1596, SEQ ID NO: 1528, SEQ ID NO: 1534, SEQ ID NO:1540, SEQ ID NO: 1546, SEQ ID NO: 1552, SEQ ID NO: 1558, SEQ ID NO:1564, SEQ ID NO: 1570, SEQ ID NO: 1576, SEQ ID NO: 1582, or SEQ ID NO:1588 as shown in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L,a light chain CDR2 comprising the amino acid sequence of any one of theLCDR2s in SEQ ID NO: 401, SEQ ID NO: 407, SEQ ID NO: 413, SEQ ID NO:419, SEQ ID NO: 425, SEQ ID NO: 431, SEQ ID NO: 437, SEQ ID NO: 443, SEQID NO: 449, SEQ ID NO: 455, SEQ ID NO: 461, SEQ ID NO: 467, SEQ ID NO:473, SEQ ID NO: 479, SEQ ID NO: 485, SEQ ID NO: 491, SEQ ID NO: 497, SEQID NO: 503, SEQ ID NO: 509, SEQ ID NO: 515, SEQ ID NO: 521, SEQ ID NO:527, SEQ ID NO: 533, SEQ ID NO: 539, SEQ ID NO: 545, SEQ ID NO: 551, SEQID NO: 557, SEQ ID NO: 563, SEQ ID NO: 569, SEQ ID NO: 575, SEQ ID NO:581, SEQ ID NO: 587, SEQ ID NO: 593, SEQ ID NO: 599, SEQ ID NO: 605, SEQID NO: 611, SEQ ID NO: 617, SEQ ID NO: 623, SEQ ID NO: 629, SEQ ID NO:635, SEQ ID NO: 641, SEQ ID NO: 647, SEQ ID NO: 653, SEQ ID NO: 659, SEQID NO: 665, SEQ ID NO: 671, SEQ ID NO: 677, SEQ ID NO: 683, SEQ ID NO:689, SEQ ID NO: 695, SEQ ID NO: 701, SEQ ID NO: 707, SEQ ID NO: 713, SEQID NO: 719, SEQ ID NO: 725, SEQ ID NO: 731, SEQ ID NO: 737, SEQ ID NO:743, SEQ ID NO: 749, SEQ ID NO: 755, SEQ ID NO: 761, SEQ ID NO: 767, SEQID NO: 773, SEQ ID NO: 779, SEQ ID NO: 785, SEQ ID NO: 791, SEQ ID NO:797, SEQ ID NO: 803, SEQ ID NO: 809, SEQ ID NO: 815, SEQ ID NO: 821, SEQID NO: 827, SEQ ID NO: 833, SEQ ID NO: 839, SEQ ID NO: 845, SEQ ID NO:851, SEQ ID NO: 857, SEQ ID NO: 863, SEQ ID NO: 869, SEQ ID NO: 875, SEQID NO: 881, SEQ ID NO: 887, SEQ ID NO: 893, SEQ ID NO: 899, SEQ ID NO:905, SEQ ID NO: 911, SEQ ID NO: 917, SEQ ID NO: 923, SEQ ID NO: 929, SEQID NO: 935, SEQ ID NO: 941, SEQ ID NO: 947, SEQ ID NO: 953, SEQ ID NO:959, SEQ ID NO: 965, SEQ ID NO: 971, SEQ ID NO: 977, SEQ ID NO: 983, SEQID NO: 989, SEQ ID NO: 995, SEQ ID NO: 1001, SEQ ID NO: 1007, SEQ ID NO:1013, SEQ ID NO: 1019, SEQ ID NO: 1025, SEQ ID NO: 1031, SEQ ID NO:1037, SEQ ID NO: 1043, SEQ ID NO: 1049, SEQ ID NO: 1055, SEQ ID NO:1061, SEQ ID NO: 1067, SEQ ID NO: 1073, SEQ ID NO: 1079, SEQ ID NO:1085, SEQ ID NO: 1091, SEQ ID NO: 1097, SEQ ID NO: 1103, SEQ ID NO:1109, SEQ ID NO: 1115, SEQ ID NO: 1121, SEQ ID NO: 1127, SEQ ID NO:1133, SEQ ID NO: 1139, SEQ ID NO: 1145, SEQ ID NO: 1151, SEQ ID NO:1157, SEQ ID NO: 1163, SEQ ID NO: 1169, SEQ ID NO: 1175, SEQ ID NO:1181, SEQ ID NO: 1187, SEQ ID NO: 1193, SEQ ID NO: 1199, SEQ ID NO:1205, SEQ ID NO: 1211, SEQ ID NO: 1217, SEQ ID NO: 1223, SEQ ID NO:1229, SEQ ID NO: 1235, SEQ ID NO: 1241, SEQ ID NO: 1247, SEQ ID NO:1253, SEQ ID NO: 1259, SEQ ID NO: 1265, SEQ ID NO: 1271, SEQ ID NO:1277, SEQ ID NO: 1283, SEQ ID NO: 1289, SEQ ID NO: 1295, SEQ ID NO:1301, SEQ ID NO: 1307, SEQ ID NO: 1313, SEQ ID NO: 1319, SEQ ID NO:1325, SEQ ID NO: 1331, SEQ ID NO: 1337, SEQ ID NO: 1343, SEQ ID NO:1349, SEQ ID NO: 1355, SEQ ID NO: 1361, SEQ ID NO: 1367, SEQ ID NO:1373, SEQ ID NO: 1379, SEQ ID NO: 1385, SEQ ID NO: 1391, SEQ ID NO:1397, SEQ ID NO: 1403, SEQ ID NO: 1409, SEQ ID NO: 1415, SEQ ID NO:1421, SEQ ID NO: 1427, SEQ ID NO: 1433, SEQ ID NO: 1439, SEQ ID NO:1445, SEQ ID NO: 1451, SEQ ID NO: 1457, SEQ ID NO: 1463, SEQ ID NO:1469, SEQ ID NO: 1475, SEQ ID NO: 1481, SEQ ID NO: 1487, SEQ ID NO:1493, SEQ ID NO: 1499, SEQ ID NO: 1505, SEQ ID NO: 1511, SEQ ID NO:1517, SEQ ID NO: 1523, SEQ ID NO: 1597, SEQ ID NO: 1529, SEQ ID NO:1535, SEQ ID NO: 1541, SEQ ID NO: 1547, SEQ ID NO: 1553, SEQ ID NO:1559, SEQ ID NO: 1565, SEQ ID NO: 1571, SEQ ID NO: 1577, SEQ ID NO:1583, or SEQ ID NO: 1589 as shown in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G,3H, 3I, 3J, 3K, or 3L, and a light chain CDR3 comprising the amino acidsequence of any one of the LCDR3s in SEQ ID NO: 402, SEQ ID NO: 408, SEQID NO: 414, SEQ ID NO: 420, SEQ ID NO: 426, SEQ ID NO: 432, SEQ ID NO:438, SEQ ID NO: 444, SEQ ID NO: 450, SEQ ID NO: 456, SEQ ID NO: 462, SEQID NO: 468, SEQ ID NO: 474, SEQ ID NO: 480, SEQ ID NO: 486, SEQ ID NO:492, SEQ ID NO: 498, SEQ ID NO: 504, SEQ ID NO: 510, SEQ ID NO: 516, SEQID NO: 522, SEQ ID NO: 528, SEQ ID NO: 534, SEQ ID NO: 540, SEQ ID NO:546, SEQ ID NO: 552, SEQ ID NO: 558, SEQ ID NO: 564, SEQ ID NO: 570, SEQID NO: 576, SEQ ID NO: 582, SEQ ID NO: 588, SEQ ID NO: 594, SEQ ID NO:600, SEQ ID NO: 606, SEQ ID NO: 612, SEQ ID NO: 618, SEQ ID NO: 624, SEQID NO: 630, SEQ ID NO: 636, SEQ ID NO: 642, SEQ ID NO: 648, SEQ ID NO:654, SEQ ID NO: 660, SEQ ID NO: 666, SEQ ID NO: 672, SEQ ID NO: 678, SEQID NO: 684, SEQ ID NO: 690, SEQ ID NO: 696, SEQ ID NO: 702, SEQ ID NO:708, SEQ ID NO: 714, SEQ ID NO: 720, SEQ ID NO: 726, SEQ ID NO: 732, SEQID NO: 738, SEQ ID NO: 744, SEQ ID NO: 750, SEQ ID NO: 756, SEQ ID NO:762, SEQ ID NO: 768, SEQ ID NO: 774, SEQ ID NO: 780, SEQ ID NO: 786, SEQID NO: 792, SEQ ID NO: 798, SEQ ID NO: 804, SEQ ID NO: 810, SEQ ID NO:816, SEQ ID NO: 822, SEQ ID NO: 828, SEQ ID NO: 834, SEQ ID NO: 840, SEQID NO: 846, SEQ ID NO: 852, SEQ ID NO: 858, SEQ ID NO: 864, SEQ ID NO:870, SEQ ID NO: 876, SEQ ID NO: 882, SEQ ID NO: 888, SEQ ID NO: 894, SEQID NO: 900, SEQ ID NO: 906, SEQ ID NO: 912, SEQ ID NO: 918, SEQ ID NO:924, SEQ ID NO: 930, SEQ ID NO: 936, SEQ ID NO: 942, SEQ ID NO: 948, SEQID NO: 954, SEQ ID NO: 960, SEQ ID NO: 966, SEQ ID NO: 972, SEQ ID NO:978, SEQ ID NO: 984, SEQ ID NO: 990, SEQ ID NO: 996, SEQ ID NO: 1002,SEQ ID NO: 1008, SEQ ID NO: 1014, SEQ ID NO: 1020, SEQ ID NO: 1026, SEQID NO: 1032, SEQ ID NO: 1038, SEQ ID NO: 1044, SEQ ID NO: 1050, SEQ IDNO: 1056, SEQ ID NO: 1062, SEQ ID NO: 1068, SEQ ID NO: 1074, SEQ ID NO:1080, SEQ ID NO: 1086, SEQ ID NO: 1092, SEQ ID NO: 1098, SEQ ID NO:1104, SEQ ID NO: 1110, SEQ ID NO: 1116, SEQ ID NO: 1122, SEQ ID NO:1128, SEQ ID NO: 1134, SEQ ID NO: 1140, SEQ ID NO: 1146, SEQ ID NO:1152, SEQ ID NO: 1158, SEQ ID NO: 1164, SEQ ID NO: 1170, SEQ ID NO:1176, SEQ ID NO: 1182, SEQ ID NO: 1188, SEQ ID NO: 1194, SEQ ID NO:1200, SEQ ID NO: 1206, SEQ ID NO: 1212, SEQ ID NO: 1218, SEQ ID NO:1224, SEQ ID NO: 1230, SEQ ID NO: 1236, SEQ ID NO: 1242, SEQ ID NO:1248, SEQ ID NO: 1254, SEQ ID NO: 1260, SEQ ID NO: 1266, SEQ ID NO:1272, SEQ ID NO: 1278, SEQ ID NO: 1284, SEQ ID NO: 1290, SEQ ID NO:1296, SEQ ID NO: 1302, SEQ ID NO: 1308, SEQ ID NO: 1314, SEQ ID NO:1320, SEQ ID NO: 1326, SEQ ID NO: 1332, SEQ ID NO: 1338, SEQ ID NO:1344, SEQ ID NO: 1350, SEQ ID NO: 1356, SEQ ID NO: 1362, SEQ ID NO:1368, SEQ ID NO: 1374, SEQ ID NO: 1380, SEQ ID NO: 1386, SEQ ID NO:1392, SEQ ID NO: 1398, SEQ ID NO: 1404, SEQ ID NO: 1410, SEQ ID NO:1416, SEQ ID NO: 1422, SEQ ID NO: 1428, SEQ ID NO: 1434, SEQ ID NO:1440, SEQ ID NO: 1446, SEQ ID NO: 1452, SEQ ID NO: 1458, SEQ ID NO:1464, SEQ ID NO: 1470, SEQ ID NO: 1476, SEQ ID NO: 1482, SEQ ID NO:1488, SEQ ID NO: 1494, SEQ ID NO: 1500, SEQ ID NO: 1506, SEQ ID NO:1512, SEQ ID NO: 1518, SEQ ID NO: 1524, SEQ ID NO: 1598, SEQ ID NO:1530, SEQ ID NO: 1536, SEQ ID NO: 1542, SEQ ID NO: 1548, SEQ ID NO:1554, SEQ ID NO: 1560, SEQ ID NO: 1566, SEQ ID NO: 1572, SEQ ID NO:1578, SEQ ID NO: 1584, or SEQ ID NO: 1590 as shown in FIG. 3A, 3B, 3C,3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain CDR1 comprising the amino acidsequence of any of one of the HCDR1s in SEQ ID NO: 397, SEQ ID NO: 403.SEQ ID NO: 409, SEQ ID NO: 415, SEQ ID NO: 421, SEQ ID NO: 427, SEQ IDNO: 433, SEQ ID NO: 439, SEQ ID NO: 445, SEQ ID NO: 451, SEQ ID NO: 457,SEQ ID NO: 463, SEQ ID NO: 469, SEQ ID NO: 475, SEQ ID NO: 481, SEQ IDNO: 487, SEQ ID NO: 493, SEQ ID NO: 499, SEQ ID NO: 505, SEQ ID NO: 511,SEQ ID NO: 517, SEQ ID NO: 523, SEQ ID NO: 529, SEQ ID NO: 535, SEQ IDNO: 541, SEQ ID NO: 547, SEQ ID NO: 553, SEQ ID NO: 559, SEQ ID NO: 565,SEQ ID NO: 571, SEQ ID NO: 577, SEQ ID NO: 583, SEQ ID NO: 589, SEQ IDNO: 595, SEQ ID NO: 601, SEQ ID NO: 607, SEQ ID NO: 613, SEQ ID NO: 619,SEQ ID NO: 625, SEQ ID NO: 631, SEQ ID NO: 637, SEQ ID NO: 643, SEQ IDNO: 649, SEQ ID NO: 655, SEQ ID NO: 661, SEQ ID NO: 667, SEQ ID NO: 673,SEQ ID NO: 679, SEQ ID NO: 685, SEQ ID NO: 691, SEQ ID NO: 697, SEQ IDNO: 703, SEQ ID NO: 709, SEQ ID NO: 715, SEQ ID NO: 721, SEQ ID NO: 727,SEQ ID NO: 733, SEQ ID NO: 739, SEQ ID NO: 745, SEQ ID NO: 751, SEQ IDNO: 757, SEQ ID NO: 763, SEQ ID NO: 769, SEQ ID NO: 775, SEQ ID NO: 781,SEQ ID NO: 787, SEQ ID NO: 793, SEQ ID NO: 799, SEQ ID NO: 805, SEQ IDNO: 811, SEQ ID NO: 817, SEQ ID NO: 823, SEQ ID NO: 829, SEQ ID NO: 835,SEQ ID NO: 841, SEQ ID NO: 847, SEQ ID NO: 853, SEQ ID NO: 859, SEQ IDNO: 865, SEQ ID NO: 871, SEQ ID NO: 877, SEQ ID NO: 883, SEQ ID NO: 889,SEQ ID NO: 895, SEQ ID NO: 901, SEQ ID NO: 907, SEQ ID NO: 913, SEQ IDNO: 919, SEQ ID NO: 925, SEQ ID NO: 931, SEQ ID NO: 937, SEQ ID NO: 943,SEQ ID NO: 949, SEQ ID NO: 955, SEQ ID NO: 961, SEQ ID NO: 967, SEQ IDNO: 973, SEQ ID NO: 979, SEQ ID NO: 985, SEQ ID NO: 991, SEQ ID NO: 997,SEQ ID NO: 1003, SEQ ID NO: 1009, SEQ ID NO: 1015, SEQ ID NO: 1021, SEQID NO: 1027, SEQ ID NO: 1033, SEQ ID NO: 1039, SEQ ID NO: 1045, SEQ IDNO: 1051, SEQ ID NO: 1057, SEQ ID NO: 1063, SEQ ID NO: 1069, SEQ ID NO:1075, SEQ ID NO: 1081, SEQ ID NO: 1087, SEQ ID NO: 1093, SEQ ID NO:1099, SEQ ID NO: 1105, SEQ ID NO: 1111, SEQ ID NO: 1117, SEQ ID NO:1123, SEQ ID NO: 1129, SEQ ID NO: 1135, SEQ ID NO: 1141, SEQ ID NO:1147, SEQ ID NO: 1153, SEQ ID NO: 1159, SEQ ID NO: 1165, SEQ ID NO:1171, SEQ ID NO: 1177, SEQ ID NO: 1183, SEQ ID NO: 1189, SEQ ID NO:1195, SEQ ID NO: 1201, SEQ ID NO: 1207, SEQ ID NO: 1213, SEQ ID NO:1219, SEQ ID NO: 1225, SEQ ID NO: 1231, SEQ ID NO: 1237, SEQ ID NO:1243, SEQ ID NO: 1249, SEQ ID NO: 1255, SEQ ID NO: 1261, SEQ ID NO:1267, SEQ ID NO: 1273, SEQ ID NO: 1279, SEQ ID NO: 1285, SEQ ID NO:1291, SEQ ID NO: 1297, SEQ ID NO: 1303, SEQ ID NO: 1309, SEQ ID NO:1315, SEQ ID NO: 1321, SEQ ID NO: 1327, SEQ ID NO: 1333, SEQ ID NO:1339, SEQ ID NO: 1345, SEQ ID NO: 1351, SEQ ID NO: 1357, SEQ ID NO:1363, SEQ ID NO: 1369, SEQ ID NO: 1375, SEQ ID NO: 1381, SEQ ID NO:1387, SEQ ID NO: 1393, SEQ ID NO: 1399, SEQ ID NO: 1405, SEQ ID NO:1411, SEQ ID NO: 1417, SEQ ID NO: 1423, SEQ ID NO: 1429, SEQ ID NO:1435, SEQ ID NO: 1441, SEQ ID NO: 1447, SEQ ID NO: 1453, SEQ ID NO:1459, SEQ ID NO: 1465, SEQ ID NO: 1471, SEQ ID NO: 1477, SEQ ID NO:1483, SEQ ID NO: 1489, SEQ ID NO: 1495, SEQ ID NO: 1501, SEQ ID NO:1507, SEQ ID NO: 1513, SEQ ID NO: 1519, SEQ ID NO: 1593, SEQ ID NO: 1525SEQ ID NO: 1531, SEQ ID NO: 1537, SEQ ID NO: 1543, SEQ ID NO: 1549, SEQID NO: 1555, SEQ ID NO: 1561, SEQ ID NO: 1567, SEQ ID NO: 1573, SEQ IDNO: 1579, or SEQ ID NO: 1585 as shown in 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H,3I, 3J, 3K, or 3L, a heavy chain CDR2 comprising the amino acid sequenceof any one of the HCDR2s in SEQ ID NO: 398, SEQ ID NO: 404, SEQ ID NO:410, SEQ ID NO: 416, SEQ ID NO: 422, SEQ ID NO: 428, SEQ ID NO: 434, SEQID NO: 440, SEQ ID NO: 446, SEQ ID NO: 452, SEQ ID NO: 458, SEQ ID NO:464, SEQ ID NO: 470, SEQ ID NO: 476, SEQ ID NO: 482, SEQ ID NO: 488, SEQID NO: 494, SEQ ID NO: 500, SEQ ID NO: 506, SEQ ID NO: 512, SEQ ID NO:518, SEQ ID NO: 524, SEQ ID NO: 530, SEQ ID NO: 536, SEQ ID NO: 542, SEQID NO: 548, SEQ ID NO: 554, SEQ ID NO: 560, SEQ ID NO: 566, SEQ ID NO:572, SEQ ID NO: 578, SEQ ID NO: 584, SEQ ID NO: 590, SEQ ID NO: 596, SEQID NO: 602, SEQ ID NO: 608, SEQ ID NO: 614, SEQ ID NO: 620, SEQ ID NO:626, SEQ ID NO: 632, SEQ ID NO: 638, SEQ ID NO: 644, SEQ ID NO: 650, SEQID NO: 656, SEQ ID NO: 662, SEQ ID NO: 668, SEQ ID NO: 674, SEQ ID NO:680, SEQ ID NO: 686, SEQ ID NO: 692, SEQ ID NO: 698, SEQ ID NO: 704, SEQID NO: 710, SEQ ID NO: 716, SEQ ID NO: 722, SEQ ID NO: 728, SEQ ID NO:734, SEQ ID NO: 740, SEQ ID NO: 746, SEQ ID NO: 752, SEQ ID NO: 758, SEQID NO: 764, SEQ ID NO: 770, SEQ ID NO: 776, SEQ ID NO: 782, SEQ ID NO:788, SEQ ID NO: 794, SEQ ID NO: 800, SEQ ID NO: 806, SEQ ID NO: 812, SEQID NO: 818, SEQ ID NO: 824, SEQ ID NO: 830, SEQ ID NO: 836, SEQ ID NO:842, SEQ ID NO: 848, SEQ ID NO: 854, SEQ ID NO: 860, SEQ ID NO: 866, SEQID NO: 872, SEQ ID NO: 878, SEQ ID NO: 884, SEQ ID NO: 890, SEQ ID NO:896, SEQ ID NO: 902, SEQ ID NO: 908, SEQ ID NO: 914, SEQ ID NO: 920, SEQID NO: 926, SEQ ID NO: 932, SEQ ID NO: 938, SEQ ID NO: 944, SEQ ID NO:950, SEQ ID NO: 956, SEQ ID NO: 962, SEQ ID NO: 968, SEQ ID NO: 974, SEQID NO: 980, SEQ ID NO: 986, SEQ ID NO: 992, SEQ ID NO: 998, SEQ ID NO:1004, SEQ ID NO: 1010, SEQ ID NO: 1016, SEQ ID NO: 1022, SEQ ID NO:1028, SEQ ID NO: 1034, SEQ ID NO: 1040, SEQ ID NO: 1046, SEQ ID NO:1052, SEQ ID NO: 1058, SEQ ID NO: 1064, SEQ ID NO: 1070, SEQ ID NO:1076, SEQ ID NO: 1082, SEQ ID NO: 1088, SEQ ID NO: 1094, SEQ ID NO:1100, SEQ ID NO: 1106, SEQ ID NO: 1112, SEQ ID NO: 1118, SEQ ID NO:1124, SEQ ID NO: 1130, SEQ ID NO: 1136, SEQ ID NO: 1142, SEQ ID NO:1148, SEQ ID NO: 1154, SEQ ID NO: 1160, SEQ ID NO: 1166, SEQ ID NO:1172, SEQ ID NO: 1178, SEQ ID NO: 1184, SEQ ID NO: 1190, SEQ ID NO:1196, SEQ ID NO: 1202, SEQ ID NO: 1208, SEQ ID NO: 1214, SEQ ID NO:1220, SEQ ID NO: 1226, SEQ ID NO: 1232, SEQ ID NO: 1238, SEQ ID NO:1244, SEQ ID NO: 1250, SEQ ID NO: 1256, SEQ ID NO: 1262, SEQ ID NO:1268, SEQ ID NO: 1274, SEQ ID NO: 1280, SEQ ID NO: 1286, SEQ ID NO:1292, SEQ ID NO: 1298, SEQ ID NO: 1304, SEQ ID NO: 1310, SEQ ID NO:1316, SEQ ID NO: 1322, SEQ ID NO: 1328, SEQ ID NO: 1334, SEQ ID NO:1340, SEQ ID NO: 1346, SEQ ID NO: 1352, SEQ ID NO: 1358, SEQ ID NO:1364, SEQ ID NO: 1370, SEQ ID NO: 1376, SEQ ID NO: 1382, SEQ ID NO:1388, SEQ ID NO: 1394, SEQ ID NO: 1400, SEQ ID NO: 1406, SEQ ID NO:1412, SEQ ID NO: 1418, SEQ ID NO: 1424, SEQ ID NO: 1430, SEQ ID NO:1436, SEQ ID NO: 1442, SEQ ID NO: 1448, SEQ ID NO: 1454, SEQ ID NO:1460, SEQ ID NO: 1466, SEQ ID NO: 1472, SEQ ID NO: 1478, SEQ ID NO:1484, SEQ ID NO: 1490, SEQ ID NO: 1496, SEQ ID NO: 1502, SEQ ID NO:1508, SEQ ID NO: 1514, SEQ ID NO: 1520, SEQ ID NO: 1594, SEQ ID NO:1526, SEQ ID NO: 1532, SEQ ID NO: 1538, SEQ ID NO: 1544, SEQ ID NO:1550, SEQ ID NO: 1556, SEQ ID NO: 1562, SEQ ID NO: 1568, SEQ ID NO:1574, SEQ ID NO: 1580, or SEQ ID NO: 1586 as shown in FIG. 3A, 3B, 3C,3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, a heavy chain CDR3 comprising theamino acid sequence of any one of the HCDR3s in SEQ ID NO: 399, SEQ IDNO: 405, SEQ ID NO: 411, SEQ ID NO: 417, SEQ ID NO: 423, SEQ ID NO: 429,SEQ ID NO: 435, SEQ ID NO: 441, SEQ ID NO: 447, SEQ ID NO: 453, SEQ IDNO: 459, SEQ ID NO: 465, SEQ ID NO: 471, SEQ ID NO: 477, SEQ ID NO: 483,SEQ ID NO: 489, SEQ ID NO: 495, SEQ ID NO: 501, SEQ ID NO: 507, SEQ IDNO: 513, SEQ ID NO: 519, SEQ ID NO: 525, SEQ ID NO: 531, SEQ ID NO: 537,SEQ ID NO: 543, SEQ ID NO: 549, SEQ ID NO: 555, SEQ ID NO: 561, SEQ IDNO: 567, SEQ ID NO: 573, SEQ ID NO: 579, SEQ ID NO: 585, SEQ ID NO: 591,SEQ ID NO: 597, SEQ ID NO: 603, SEQ ID NO: 609, SEQ ID NO: 615, SEQ IDNO: 621, SEQ ID NO: 627, SEQ ID NO: 633, SEQ ID NO: 639, SEQ ID NO: 645,SEQ ID NO: 651, SEQ ID NO: 657, SEQ ID NO: 663, SEQ ID NO: 669, SEQ IDNO: 675, SEQ ID NO: 681, SEQ ID NO: 687, SEQ ID NO: 693, SEQ ID NO: 699,SEQ ID NO: 705, SEQ ID NO: 711, SEQ ID NO: 717, SEQ ID NO: 723, SEQ IDNO: 729, SEQ ID NO: 735, SEQ ID NO: 741, SEQ ID NO: 747, SEQ ID NO: 753,SEQ ID NO: 759, SEQ ID NO: 765, SEQ ID NO: 771, SEQ ID NO: 777, SEQ IDNO: 783, SEQ ID NO: 789, SEQ ID NO: 795, SEQ ID NO: 801, SEQ ID NO: 807,SEQ ID NO: 813, SEQ ID NO: 819, SEQ ID NO: 825, SEQ ID NO: 831, SEQ IDNO: 837, SEQ ID NO: 843, SEQ ID NO: 849, SEQ ID NO: 855, SEQ ID NO: 861,SEQ ID NO: 867, SEQ ID NO: 873, SEQ ID NO: 879, SEQ ID NO: 885, SEQ IDNO: 891, SEQ ID NO: 897, SEQ ID NO: 903, SEQ ID NO: 909, SEQ ID NO: 915,SEQ ID NO: 921, SEQ ID NO: 927, SEQ ID NO: 933, SEQ ID NO: 939, SEQ IDNO: 945, SEQ ID NO: 951, SEQ ID NO: 957, SEQ ID NO: 963, SEQ ID NO: 969,SEQ ID NO: 975, SEQ ID NO: 981, SEQ ID NO: 987, SEQ ID NO: 993, SEQ IDNO: 999, SEQ ID NO: 1005, SEQ ID NO: 1011, SEQ ID NO: 1017, SEQ ID NO:1023, SEQ ID NO: 1029, SEQ ID NO: 1035, SEQ ID NO: 1041, SEQ ID NO:1047, SEQ ID NO: 1053, SEQ ID NO: 1059, SEQ ID NO: 1065, SEQ ID NO:1071, SEQ ID NO: 1077, SEQ ID NO: 1083, SEQ ID NO: 1089, SEQ ID NO:1095, SEQ ID NO: 1101, SEQ ID NO: 1107, SEQ ID NO: 1113, SEQ ID NO:1119, SEQ ID NO: 1125, SEQ ID NO: 1131, SEQ ID NO: 1137, SEQ ID NO:1143, SEQ ID NO: 1149, SEQ ID NO: 1155, SEQ ID NO: 1161, SEQ ID NO:1167, SEQ ID NO: 1173, SEQ ID NO: 1179, SEQ ID NO: 1185, SEQ ID NO:1191, SEQ ID NO: 1197, SEQ ID NO: 1203, SEQ ID NO: 1209, SEQ ID NO:1215, SEQ ID NO: 1221, SEQ ID NO: 1227, SEQ ID NO: 1233, SEQ ID NO:1239, SEQ ID NO: 1245, SEQ ID NO: 1251, SEQ ID NO: 1257, SEQ ID NO:1263, SEQ ID NO: 1269, SEQ ID NO: 1275, SEQ ID NO: 1281, SEQ ID NO:1287, SEQ ID NO: 1293, SEQ ID NO: 1299, SEQ ID NO: 1305, SEQ ID NO:1311, SEQ ID NO: 1317, SEQ ID NO: 1323, SEQ ID NO: 1329, SEQ ID NO:1335, SEQ ID NO: 1341, SEQ ID NO: 1347, SEQ ID NO: 1353, SEQ ID NO:1359, SEQ ID NO: 1365, SEQ ID NO: 1371, SEQ ID NO: 1377, SEQ ID NO:1383, SEQ ID NO: 1389, SEQ ID NO: 1395, SEQ ID NO: 1401, SEQ ID NO:1407, SEQ ID NO: 1413, SEQ ID NO: 1419, SEQ ID NO: 1425, SEQ ID NO:1431, SEQ ID NO: 1437, SEQ ID NO: 1443, SEQ ID NO: 1449, SEQ ID NO:1455, SEQ ID NO: 1461, SEQ ID NO: 1467, SEQ ID NO: 1473, SEQ ID NO:1479, SEQ ID NO: 1485, SEQ ID NO: 1491, SEQ ID NO: 1497, SEQ ID NO:1503, SEQ ID NO: 1509, SEQ ID NO: 1515, SEQ ID NO: 1521, SEQ ID NO:1595, SEQ ID NO: 1527, SEQ ID NO: 1533, SEQ ID NO: 1539, SEQ ID NO:1545, SEQ ID NO: 1551, SEQ ID NO: 1557, SEQ ID NO: 1563, SEQ ID NO:1569, SEQ ID NO: 1575, SEQ ID NO: 1581, or SEQ ID NO: 1587 as shown inin FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, a light chainCDR1 comprising the amino acid sequence of any one of the LCDR1s in SEQID NO: 400, SEQ ID NO: 406, SEQ ID NO: 412, SEQ ID NO: 418, SEQ ID NO:424, SEQ ID NO: 430, SEQ ID NO: 436, SEQ ID NO: 442, SEQ ID NO: 448, SEQID NO: 454, SEQ ID NO: 460, SEQ ID NO: 466, SEQ ID NO: 472, SEQ ID NO:478, SEQ ID NO: 484, SEQ ID NO: 490, SEQ ID NO: 496, SEQ ID NO: 502, SEQID NO: 508, SEQ ID NO: 514, SEQ ID NO: 520, SEQ ID NO: 526, SEQ ID NO:532, SEQ ID NO: 538, SEQ ID NO: 544, SEQ ID NO: 550, SEQ ID NO: 556, SEQID NO: 562, SEQ ID NO: 568, SEQ ID NO: 574, SEQ ID NO: 580, SEQ ID NO:586, SEQ ID NO: 592, SEQ ID NO: 598, SEQ ID NO: 604, SEQ ID NO: 610, SEQID NO: 616, SEQ ID NO: 622, SEQ ID NO: 628, SEQ ID NO: 634, SEQ ID NO:640, SEQ ID NO: 646, SEQ ID NO: 652, SEQ ID NO: 658, SEQ ID NO: 664, SEQID NO: 670, SEQ ID NO: 676, SEQ ID NO: 682, SEQ ID NO: 688, SEQ ID NO:694, SEQ ID NO: 700, SEQ ID NO: 706, SEQ ID NO: 712, SEQ ID NO: 718, SEQID NO: 724, SEQ ID NO: 730, SEQ ID NO: 736, SEQ ID NO: 742, SEQ ID NO:748, SEQ ID NO: 754, SEQ ID NO: 760, SEQ ID NO: 766, SEQ ID NO: 772, SEQID NO: 778, SEQ ID NO: 784, SEQ ID NO: 790, SEQ ID NO: 796, SEQ ID NO:802, SEQ ID NO: 808, SEQ ID NO: 814, SEQ ID NO: 820, SEQ ID NO: 826, SEQID NO: 832, SEQ ID NO: 838, SEQ ID NO: 844, SEQ ID NO: 850, SEQ ID NO:856, SEQ ID NO: 862, SEQ ID NO: 868, SEQ ID NO: 874, SEQ ID NO: 880, SEQID NO: 886, SEQ ID NO: 892, SEQ ID NO: 898, SEQ ID NO: 904, SEQ ID NO:910, SEQ ID NO: 916, SEQ ID NO: 922, SEQ ID NO: 928, SEQ ID NO: 934, SEQID NO: 940, SEQ ID NO: 946, SEQ ID NO: 952, SEQ ID NO: 958, SEQ ID NO:964, SEQ ID NO: 970, SEQ ID NO: 976, SEQ ID NO: 982, SEQ ID NO: 988, SEQID NO: 994, SEQ ID NO: 1000, SEQ ID NO: 1006, SEQ ID NO: 1012, SEQ IDNO: 1018, SEQ ID NO: 1024, SEQ ID NO: 1030, SEQ ID NO: 1036, SEQ ID NO:1042, SEQ ID NO: 1048, SEQ ID NO: 1054, SEQ ID NO: 1060, SEQ ID NO:1066, SEQ ID NO: 1072, SEQ ID NO: 1078, SEQ ID NO: 1084, SEQ ID NO:1090, SEQ ID NO: 1096, SEQ ID NO: 1102, SEQ ID NO: 1108, SEQ ID NO:1114, SEQ ID NO: 1120, SEQ ID NO: 1126, SEQ ID NO: 1132, SEQ ID NO:1138, SEQ ID NO: 1144, SEQ ID NO: 1150, SEQ ID NO: 1156, SEQ ID NO:1162, SEQ ID NO: 1168, SEQ ID NO: 1174, SEQ ID NO: 1180, SEQ ID NO:1186, SEQ ID NO: 1192, SEQ ID NO: 1198, SEQ ID NO: 1204, SEQ ID NO:1210, SEQ ID NO: 1216, SEQ ID NO: 1222, SEQ ID NO: 1228, SEQ ID NO:1234, SEQ ID NO: 1240, SEQ ID NO: 1246, SEQ ID NO: 1252, SEQ ID NO:1258, SEQ ID NO: 1264, SEQ ID NO: 1270, SEQ ID NO: 1276, SEQ ID NO:1282, SEQ ID NO: 1288, SEQ ID NO: 1294, SEQ ID NO: 1300, SEQ ID NO:1306, SEQ ID NO: 1312, SEQ ID NO: 1318, SEQ ID NO: 1324, SEQ ID NO:1330, SEQ ID NO: 1336, SEQ ID NO: 1342, SEQ ID NO: 1348, SEQ ID NO:1354, SEQ ID NO: 1360, SEQ ID NO: 1366, SEQ ID NO: 1372, SEQ ID NO:1378, SEQ ID NO: 1384, SEQ ID NO: 1390, SEQ ID NO: 1396, SEQ ID NO:1402, SEQ ID NO: 1408, SEQ ID NO: 1414, SEQ ID NO: 1420, SEQ ID NO:1426, SEQ ID NO: 1432, SEQ ID NO: 1438, SEQ ID NO: 1444, SEQ ID NO:1450. SEQ ID NO: 1456, SEQ ID NO: 1462, SEQ ID NO: 1468, SEQ ID NO:1474, SEQ ID NO: 1480, SEQ ID NO: 1486, SEQ ID NO: 1492, SEQ ID NO:1498, SEQ ID NO: 1504, SEQ ID NO: 1510, SEQ ID NO: 1516, SEQ ID NO:1522, SEQ ID NO: 1596, SEQ ID NO: 1528, SEQ ID NO: 1534, SEQ ID NO:1540, SEQ ID NO: 1546, SEQ ID NO: 1552, SEQ ID NO: 1558, SEQ ID NO:1564, SEQ ID NO: 1570, SEQ ID NO: 1576, SEQ ID NO: 1582, or SEQ ID NO:1588 as shown in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L,a light chain CDR2 comprising the amino acid sequence of any one of theLCDR2s in SEQ ID NO: 401, SEQ ID NO: 407, SEQ ID NO: 413, SEQ ID NO:419, SEQ ID NO: 425, SEQ ID NO: 431, SEQ ID NO: 437, SEQ ID NO: 443, SEQID NO: 449, SEQ ID NO: 455, SEQ ID NO: 461, SEQ ID NO: 467, SEQ ID NO:473, SEQ ID NO: 479, SEQ ID NO: 485, SEQ ID NO: 491, SEQ ID NO: 497, SEQID NO: 503, SEQ ID NO: 509, SEQ ID NO: 515, SEQ ID NO: 521, SEQ ID NO:527, SEQ ID NO: 533, SEQ ID NO: 539, SEQ ID NO: 545, SEQ ID NO: 551, SEQID NO: 557, SEQ ID NO: 563, SEQ ID NO: 569, SEQ ID NO: 575, SEQ ID NO:581, SEQ ID NO: 587, SEQ ID NO: 593, SEQ ID NO: 599, SEQ ID NO: 605, SEQID NO: 611, SEQ ID NO: 617, SEQ ID NO: 623, SEQ ID NO: 629, SEQ ID NO:635, SEQ ID NO: 641, SEQ ID NO: 647, SEQ ID NO: 653, SEQ ID NO: 659, SEQID NO: 665, SEQ ID NO: 671, SEQ ID NO: 677, SEQ ID NO: 683, SEQ ID NO:689, SEQ ID NO: 695, SEQ ID NO: 701, SEQ ID NO: 707, SEQ ID NO: 713, SEQID NO: 719, SEQ ID NO: 725, SEQ ID NO: 731, SEQ ID NO: 737, SEQ ID NO:743, SEQ ID NO: 749, SEQ ID NO: 755, SEQ ID NO: 761, SEQ ID NO: 767, SEQID NO: 773, SEQ ID NO: 779, SEQ ID NO: 785, SEQ ID NO: 791, SEQ ID NO:797, SEQ ID NO: 803, SEQ ID NO: 809, SEQ ID NO: 815, SEQ ID NO: 821, SEQID NO: 827, SEQ ID NO: 833, SEQ ID NO: 839, SEQ ID NO: 845, SEQ ID NO:851, SEQ ID NO: 857, SEQ ID NO: 863, SEQ ID NO: 869, SEQ ID NO: 875, SEQID NO: 881, SEQ ID NO: 887, SEQ ID NO: 893, SEQ ID NO: 899, SEQ ID NO:905, SEQ ID NO: 911, SEQ ID NO: 917, SEQ ID NO: 923, SEQ ID NO: 929, SEQID NO: 935, SEQ ID NO: 941, SEQ ID NO: 947, SEQ ID NO: 953, SEQ ID NO:959, SEQ ID NO: 965, SEQ ID NO: 971, SEQ ID NO: 977, SEQ ID NO: 983, SEQID NO: 989, SEQ ID NO: 995, SEQ ID NO: 1001, SEQ ID NO: 1007, SEQ ID NO:1013, SEQ ID NO: 1019, SEQ ID NO: 1025, SEQ ID NO: 1031, SEQ ID NO:1037, SEQ ID NO: 1043, SEQ ID NO: 1049, SEQ ID NO: 1055, SEQ ID NO:1061, SEQ ID NO: 1067, SEQ ID NO: 1073, SEQ ID NO: 1079, SEQ ID NO:1085, SEQ ID NO: 1091, SEQ ID NO: 1097, SEQ ID NO: 1103, SEQ ID NO:1109, SEQ ID NO: 1115, SEQ ID NO: 1121, SEQ ID NO: 1127, SEQ ID NO:1133, SEQ ID NO: 1139, SEQ ID NO: 1145, SEQ ID NO: 1151, SEQ ID NO:1157, SEQ ID NO: 1163, SEQ ID NO: 1169, SEQ ID NO: 1175, SEQ ID NO:1181, SEQ ID NO: 1187, SEQ ID NO: 1193, SEQ ID NO: 1199, SEQ ID NO:1205, SEQ ID NO: 1211, SEQ ID NO: 1217, SEQ ID NO: 1223, SEQ ID NO:1229, SEQ ID NO: 1235, SEQ ID NO: 1241, SEQ ID NO: 1247, SEQ ID NO:1253, SEQ ID NO: 1259, SEQ ID NO: 1265, SEQ ID NO: 1271, SEQ ID NO:1277, SEQ ID NO: 1283, SEQ ID NO: 1289, SEQ ID NO: 1295, SEQ ID NO:1301, SEQ ID NO: 1307, SEQ ID NO: 1313, SEQ ID NO: 1319, SEQ ID NO:1325, SEQ ID NO: 1331, SEQ ID NO: 1337, SEQ ID NO: 1343, SEQ ID NO:1349, SEQ ID NO: 1355, SEQ ID NO: 1361, SEQ ID NO: 1367, SEQ ID NO:1373, SEQ ID NO: 1379, SEQ ID NO: 1385, SEQ ID NO: 1391, SEQ ID NO:1397, SEQ ID NO: 1403, SEQ ID NO: 1409, SEQ ID NO: 1415, SEQ ID NO:1421, SEQ ID NO: 1427, SEQ ID NO: 1433, SEQ ID NO: 1439, SEQ ID NO:1445, SEQ ID NO: 1451, SEQ ID NO: 1457, SEQ ID NO: 1463, SEQ ID NO:1469, SEQ ID NO: 1475, SEQ ID NO: 1481, SEQ ID NO: 1487, SEQ ID NO:1493, SEQ ID NO: 1499, SEQ ID NO: 1505, SEQ ID NO: 1511, SEQ ID NO:1517, SEQ ID NO: 1523, SEQ ID NO: 1597, SEQ ID NO: 1529, SEQ ID NO:1535, SEQ ID NO: 1541, SEQ ID NO: 1547, SEQ ID NO: 1553, SEQ ID NO:1559, SEQ ID NO: 1565, SEQ ID NO: 1571, SEQ ID NO: 1577, SEQ ID NO:1583, or SEQ ID NO: 1589 as shown in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G,3H, 3I, 3J, 3K, or 3L, and a light chain CDR3 comprising the amino acidsequence of any one of the LCDR3s in SEQ ID NO: 402, SEQ ID NO: 408, SEQID NO: 414, SEQ ID NO: 420, SEQ ID NO: 426, SEQ ID NO: 432, SEQ ID NO:438, SEQ ID NO: 444, SEQ ID NO: 450, SEQ ID NO: 456, SEQ ID NO: 462, SEQID NO: 468, SEQ ID NO: 474, SEQ ID NO: 480, SEQ ID NO: 486, SEQ ID NO:492, SEQ ID NO: 498, SEQ ID NO: 504, SEQ ID NO: 510, SEQ ID NO: 516, SEQID NO: 522, SEQ ID NO: 528, SEQ ID NO: 534, SEQ ID NO: 540, SEQ ID NO:546, SEQ ID NO: 552, SEQ ID NO: 558, SEQ ID NO: 564, SEQ ID NO: 570, SEQID NO: 576, SEQ ID NO: 582, SEQ ID NO: 588, SEQ ID NO: 594, SEQ ID NO:600, SEQ ID NO: 606, SEQ ID NO: 612, SEQ ID NO: 618, SEQ ID NO: 624, SEQID NO: 630, SEQ ID NO: 636, SEQ ID NO: 642, SEQ ID NO: 648, SEQ ID NO:654, SEQ ID NO: 660, SEQ ID NO: 666, SEQ ID NO: 672, SEQ ID NO: 678, SEQID NO: 684, SEQ ID NO: 690, SEQ ID NO: 696, SEQ ID NO: 702, SEQ ID NO:708, SEQ ID NO: 714, SEQ ID NO: 720, SEQ ID NO: 726, SEQ ID NO: 732, SEQID NO: 738, SEQ ID NO: 744, SEQ ID NO: 750, SEQ ID NO: 756, SEQ ID NO:762, SEQ ID NO: 768, SEQ ID NO: 774, SEQ ID NO: 780, SEQ ID NO: 786, SEQID NO: 792, SEQ ID NO: 798, SEQ ID NO: 804, SEQ ID NO: 810, SEQ ID NO:816, SEQ ID NO: 822, SEQ ID NO: 828, SEQ ID NO: 834, SEQ ID NO: 840, SEQID NO: 846, SEQ ID NO: 852, SEQ ID NO: 858, SEQ ID NO: 864, SEQ ID NO:870, SEQ ID NO: 876, SEQ ID NO: 882, SEQ ID NO: 888, SEQ ID NO: 894, SEQID NO: 900, SEQ ID NO: 906, SEQ ID NO: 912, SEQ ID NO: 918, SEQ ID NO:924, SEQ ID NO: 930, SEQ ID NO: 936, SEQ ID NO: 942, SEQ ID NO: 948, SEQID NO: 954, SEQ ID NO: 960, SEQ ID NO: 966, SEQ ID NO: 972, SEQ ID NO:978, SEQ ID NO: 984, SEQ ID NO: 990, SEQ ID NO: 996, SEQ ID NO: 1002,SEQ ID NO: 1008, SEQ ID NO: 1014, SEQ ID NO: 1020, SEQ ID NO: 1026, SEQID NO: 1032, SEQ ID NO: 1038, SEQ ID NO: 1044, SEQ ID NO: 1050, SEQ IDNO: 1056, SEQ ID NO: 1062, SEQ ID NO: 1068, SEQ ID NO: 1074, SEQ ID NO:1080, SEQ ID NO: 1086, SEQ ID NO: 1092, SEQ ID NO: 1098, SEQ ID NO:1104, SEQ ID NO: 1110, SEQ ID NO: 1116, SEQ ID NO: 1122, SEQ ID NO:1128, SEQ ID NO: 1134, SEQ ID NO: 1140, SEQ ID NO: 1146, SEQ ID NO:1152, SEQ ID NO: 1158, SEQ ID NO: 1164, SEQ ID NO: 1170, SEQ ID NO:1176, SEQ ID NO: 1182, SEQ ID NO: 1188, SEQ ID NO: 1194, SEQ ID NO:1200, SEQ ID NO: 1206, SEQ ID NO: 1212, SEQ ID NO: 1218, SEQ ID NO:1224, SEQ ID NO: 1230, SEQ ID NO: 1236, SEQ ID NO: 1242, SEQ ID NO:1248, SEQ ID NO: 1254, SEQ ID NO: 1260, SEQ ID NO: 1266, SEQ ID NO:1272, SEQ ID NO: 1278, SEQ ID NO: 1284, SEQ ID NO: 1290, SEQ ID NO:1296, SEQ ID NO: 1302, SEQ ID NO: 1308, SEQ ID NO: 1314, SEQ ID NO:1320, SEQ ID NO: 1326, SEQ ID NO: 1332, SEQ ID NO: 1338, SEQ ID NO:1344, SEQ ID NO: 1350, SEQ ID NO: 1356, SEQ ID NO: 1362, SEQ ID NO:1368, SEQ ID NO: 1374, SEQ ID NO: 1380, SEQ ID NO: 1386, SEQ ID NO:1392, SEQ ID NO: 1398, SEQ ID NO: 1404, SEQ ID NO: 1410, SEQ ID NO:1416, SEQ ID NO: 1422, SEQ ID NO: 1428, SEQ ID NO: 1434, SEQ ID NO:1440, SEQ ID NO: 1446, SEQ ID NO: 1452, SEQ ID NO: 1458, SEQ ID NO:1464, SEQ ID NO: 1470, SEQ ID NO: 1476, SEQ ID NO: 1482, SEQ ID NO:1488, SEQ ID NO: 1494, SEQ ID NO: 1500, SEQ ID NO: 1506, SEQ ID NO:1512, SEQ ID NO: 1518, SEQ ID NO: 1524, SEQ ID NO: 1598, SEQ ID NO:1530, SEQ ID NO: 1536, SEQ ID NO: 1542, SEQ ID NO: 1548, SEQ ID NO:1554, SEQ ID NO: 1560, SEQ ID NO: 1566, SEQ ID NO: 1572, SEQ ID NO:1578, SEQ ID NO: 1584, or SEQ ID NO: 1590 as shown in FIG. 3A, 3B, 3C,3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, and the HCDR1, HCDR2, HCDR3,LCDR1, LCDR2, and LCDR3 are from a same clone.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain comprising the heavy chain aminoacid variable sequence in any one of SEQ ID NO. 1-SEQ ID NO: 97, SEQ IDNO: 195-SEQ ID NO: 209, or SEQ ID NO: 225-SEQ ID NO: 310 as shown inFIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Qor 2R.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a light chain comprising the light chain aminoacid variable sequence in any one of SEQ ID NO: 98-SEQ ID NO: 194, SEQID NO: 210-SEQ ID NO: 224, or SEQ ID NO: 311-SEQ ID NO: 396 as shown inFIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Qor 2R.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain comprising the heavy chain aminoacid variable sequence in any one of SEQ ID NO. 1-SEQ ID NO: 97, SEQ IDNO: 195-SEQ ID NO: 209, or SEQ ID NO: 225-SEQ ID NO: 310 as shown inFIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Qor 2R and a light chain comprising the light chain amino acid variablesequence in any one of SEQ ID NO: 98-SEQ ID NO: 194, SEQ ID NO: 210-SEQID NO: 224, or SEQ ID NO: 311-SEQ ID NO: 396 as shown in FIG. 2A, 2B,2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R.

In some embodiments, an isolated antibody comprises a heavy chain CDR1comprising the amino acid sequence of any of one of the HCDR1s in SEQ IDNO: 397, SEQ ID NO: 403. SEQ ID NO: 409, SEQ ID NO: 415, SEQ ID NO: 421,SEQ ID NO: 427, SEQ ID NO: 433, SEQ ID NO: 439, SEQ ID NO: 445, SEQ IDNO: 451, SEQ ID NO: 457, SEQ ID NO: 463, SEQ ID NO: 469, SEQ ID NO: 475,SEQ ID NO: 481, SEQ ID NO: 487, SEQ ID NO: 493, SEQ ID NO: 499, SEQ IDNO: 505, SEQ ID NO: 511, SEQ ID NO: 517, SEQ ID NO: 523, SEQ ID NO: 529,SEQ ID NO: 535, SEQ ID NO: 541, SEQ ID NO: 547, SEQ ID NO: 553, SEQ IDNO: 559, SEQ ID NO: 565, SEQ ID NO: 571, SEQ ID NO: 577, SEQ ID NO: 583,SEQ ID NO: 589, SEQ ID NO: 595, SEQ ID NO: 601, SEQ ID NO: 607, SEQ IDNO: 613, SEQ ID NO: 619, SEQ ID NO: 625, SEQ ID NO: 631, SEQ ID NO: 637,SEQ ID NO: 643, SEQ ID NO: 649, SEQ ID NO: 655, SEQ ID NO: 661, SEQ IDNO: 667, SEQ ID NO: 673, SEQ ID NO: 679, SEQ ID NO: 685, SEQ ID NO: 691,SEQ ID NO: 697, SEQ ID NO: 703, SEQ ID NO: 709, SEQ ID NO: 715, SEQ IDNO: 721, SEQ ID NO: 727, SEQ ID NO: 733, SEQ ID NO: 739, SEQ ID NO: 745,SEQ ID NO: 751, SEQ ID NO: 757, SEQ ID NO: 763, SEQ ID NO: 769, SEQ IDNO: 775, SEQ ID NO: 781, SEQ ID NO: 787, SEQ ID NO: 793, SEQ ID NO: 799,SEQ ID NO: 805, SEQ ID NO: 811, SEQ ID NO: 817, SEQ ID NO: 823, SEQ IDNO: 829, SEQ ID NO: 835, SEQ ID NO: 841, SEQ ID NO: 847, SEQ ID NO: 853,SEQ ID NO: 859, SEQ ID NO: 865, SEQ ID NO: 871, SEQ ID NO: 877, SEQ IDNO: 883, SEQ ID NO: 889, SEQ ID NO: 895, SEQ ID NO: 901, SEQ ID NO: 907,SEQ ID NO: 913, SEQ ID NO: 919, SEQ ID NO: 925, SEQ ID NO: 931, SEQ IDNO: 937, SEQ ID NO: 943, SEQ ID NO: 949, SEQ ID NO: 955, SEQ ID NO: 961,SEQ ID NO: 967, SEQ ID NO: 973, SEQ ID NO: 979, SEQ ID NO: 985, SEQ IDNO: 991, SEQ ID NO: 997, SEQ ID NO: 1003, SEQ ID NO: 1009, SEQ ID NO:1015, SEQ ID NO: 1021, SEQ ID NO: 1027, SEQ ID NO: 1033, SEQ ID NO:1039, SEQ ID NO: 1045, SEQ ID NO: 1051, SEQ ID NO: 1057, SEQ ID NO:1063, SEQ ID NO: 1069, SEQ ID NO: 1075, SEQ ID NO: 1081, SEQ ID NO:1087, SEQ ID NO: 1093, SEQ ID NO: 1099, SEQ ID NO: 1105, SEQ ID NO:1111, SEQ ID NO: 1117, SEQ ID NO: 1123, SEQ ID NO: 1129, SEQ ID NO:1135, SEQ ID NO: 1141, SEQ ID NO: 1147, SEQ ID NO: 1153, SEQ ID NO:1159, SEQ ID NO: 1165, SEQ ID NO: 1171, SEQ ID NO: 1177, SEQ ID NO:1183, SEQ ID NO: 1189, SEQ ID NO: 1195, SEQ ID NO: 1201, SEQ ID NO:1207, SEQ ID NO: 1213, SEQ ID NO: 1219, SEQ ID NO: 1225, SEQ ID NO:1231, SEQ ID NO: 1237, SEQ ID NO: 1243, SEQ ID NO: 1249, SEQ ID NO:1255, SEQ ID NO: 1261, SEQ ID NO: 1267, SEQ ID NO: 1273, SEQ ID NO:1279, SEQ ID NO: 1285, SEQ ID NO: 1291, SEQ ID NO: 1297, SEQ ID NO:1303, SEQ ID NO: 1309, SEQ ID NO: 1315, SEQ ID NO: 1321, SEQ ID NO:1327, SEQ ID NO: 1333, SEQ ID NO: 1339, SEQ ID NO: 1345, SEQ ID NO:1351, SEQ ID NO: 1357, SEQ ID NO: 1363, SEQ ID NO: 1369, SEQ ID NO:1375, SEQ ID NO: 1381, SEQ ID NO: 1387, SEQ ID NO: 1393, SEQ ID NO:1399, SEQ ID NO: 1405, SEQ ID NO: 1411, SEQ ID NO: 1417, SEQ ID NO:1423, SEQ ID NO: 1429, SEQ ID NO: 1435, SEQ ID NO: 1441, SEQ ID NO:1447, SEQ ID NO: 1453, SEQ ID NO: 1459, SEQ ID NO: 1465, SEQ ID NO:1471, SEQ ID NO: 1477, SEQ ID NO: 1483, SEQ ID NO: 1489, SEQ ID NO:1495, SEQ ID NO: 1501, SEQ ID NO: 1507, SEQ ID NO: 1513, SEQ ID NO:1519, SEQ ID NO: 1593, SEQ ID NO: 1525 SEQ ID NO: 1531, SEQ ID NO: 1537,SEQ ID NO: 1543, SEQ ID NO: 1549, SEQ ID NO: 1555, SEQ ID NO: 1561, SEQID NO: 1567, SEQ ID NO: 1573, SEQ ID NO: 1579, or SEQ ID NO: 1585 asshown in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, a heavychain CDR2 comprising the amino acid sequence of any one of the HCDR2sin SEQ ID NO: 398, SEQ ID NO: 404, SEQ ID NO: 410, SEQ ID NO: 416, SEQID NO: 422, SEQ ID NO: 428, SEQ ID NO: 434, SEQ ID NO: 440, SEQ ID NO:446, SEQ ID NO: 452, SEQ ID NO: 458, SEQ ID NO: 464, SEQ ID NO: 470, SEQID NO: 476, SEQ ID NO: 482, SEQ ID NO: 488, SEQ ID NO: 494, SEQ ID NO:500, SEQ ID NO: 506, SEQ ID NO: 512, SEQ ID NO: 518, SEQ ID NO: 524, SEQID NO: 530, SEQ ID NO: 536, SEQ ID NO: 542, SEQ ID NO: 548, SEQ ID NO:554, SEQ ID NO: 560, SEQ ID NO: 566, SEQ ID NO: 572, SEQ ID NO: 578, SEQID NO: 584, SEQ ID NO: 590, SEQ ID NO: 596, SEQ ID NO: 602, SEQ ID NO:608, SEQ ID NO: 614, SEQ ID NO: 620, SEQ ID NO: 626, SEQ ID NO: 632, SEQID NO: 638, SEQ ID NO: 644, SEQ ID NO: 650, SEQ ID NO: 656, SEQ ID NO:662, SEQ ID NO: 668, SEQ ID NO: 674, SEQ ID NO: 680, SEQ ID NO: 686, SEQID NO: 692, SEQ ID NO: 698, SEQ ID NO: 704, SEQ ID NO: 710, SEQ ID NO:716, SEQ ID NO: 722, SEQ ID NO: 728, SEQ ID NO: 734, SEQ ID NO: 740, SEQID NO: 746, SEQ ID NO: 752, SEQ ID NO: 758, SEQ ID NO: 764, SEQ ID NO:770, SEQ ID NO: 776, SEQ ID NO: 782, SEQ ID NO: 788, SEQ ID NO: 794, SEQID NO: 800, SEQ ID NO: 806, SEQ ID NO: 812, SEQ ID NO: 818, SEQ ID NO:824, SEQ ID NO: 830, SEQ ID NO: 836, SEQ ID NO: 842, SEQ ID NO: 848, SEQID NO: 854, SEQ ID NO: 860, SEQ ID NO: 866, SEQ ID NO: 872, SEQ ID NO:878, SEQ ID NO: 884, SEQ ID NO: 890, SEQ ID NO: 896, SEQ ID NO: 902, SEQID NO: 908, SEQ ID NO: 914, SEQ ID NO: 920, SEQ ID NO: 926, SEQ ID NO:932, SEQ ID NO: 938, SEQ ID NO: 944, SEQ ID NO: 950, SEQ ID NO: 956, SEQID NO: 962, SEQ ID NO: 968, SEQ ID NO: 974, SEQ ID NO: 980, SEQ ID NO:986, SEQ ID NO: 992, SEQ ID NO: 998, SEQ ID NO: 1004, SEQ ID NO: 1010,SEQ ID NO: 1016, SEQ ID NO: 1022, SEQ ID NO: 1028, SEQ ID NO: 1034, SEQID NO: 1040, SEQ ID NO: 1046, SEQ ID NO: 1052, SEQ ID NO: 1058, SEQ IDNO: 1064, SEQ ID NO: 1070, SEQ ID NO: 1076, SEQ ID NO: 1082, SEQ ID NO:1088, SEQ ID NO: 1094, SEQ ID NO: 1100, SEQ ID NO: 1106, SEQ ID NO:1112, SEQ ID NO: 1118, SEQ ID NO: 1124, SEQ ID NO: 1130, SEQ ID NO:1136, SEQ ID NO: 1142, SEQ ID NO: 1148, SEQ ID NO: 1154, SEQ ID NO:1160, SEQ ID NO: 1166, SEQ ID NO: 1172, SEQ ID NO: 1178, SEQ ID NO:1184, SEQ ID NO: 1190, SEQ ID NO: 1196, SEQ ID NO: 1202, SEQ ID NO:1208, SEQ ID NO: 1214, SEQ ID NO: 1220, SEQ ID NO: 1226, SEQ ID NO:1232, SEQ ID NO: 1238, SEQ ID NO: 1244, SEQ ID NO: 1250, SEQ ID NO:1256, SEQ ID NO: 1262, SEQ ID NO: 1268, SEQ ID NO: 1274, SEQ ID NO:1280, SEQ ID NO: 1286, SEQ ID NO: 1292, SEQ ID NO: 1298, SEQ ID NO:1304, SEQ ID NO: 1310, SEQ ID NO: 1316, SEQ ID NO: 1322, SEQ ID NO:1328, SEQ ID NO: 1334, SEQ ID NO: 1340, SEQ ID NO: 1346, SEQ ID NO:1352, SEQ ID NO: 1358, SEQ ID NO: 1364, SEQ ID NO: 1370, SEQ ID NO:1376, SEQ ID NO: 1382, SEQ ID NO: 1388, SEQ ID NO: 1394, SEQ ID NO:1400, SEQ ID NO: 1406, SEQ ID NO: 1412, SEQ ID NO: 1418, SEQ ID NO:1424, SEQ ID NO: 1430, SEQ ID NO: 1436, SEQ ID NO: 1442, SEQ ID NO:1448, SEQ ID NO: 1454, SEQ ID NO: 1460, SEQ ID NO: 1466, SEQ ID NO:1472, SEQ ID NO: 1478, SEQ ID NO: 1484, SEQ ID NO: 1490, SEQ ID NO:1496, SEQ ID NO: 1502, SEQ ID NO: 1508, SEQ ID NO: 1514, SEQ ID NO:1520, SEQ ID NO: 1594, SEQ ID NO: 1526, SEQ ID NO: 1532, SEQ ID NO:1538, SEQ ID NO: 1544, SEQ ID NO: 1550, SEQ ID NO: 1556, SEQ ID NO:1562, SEQ ID NO: 1568, SEQ ID NO: 1574, SEQ ID NO: 1580, or SEQ ID NO:1586 as shown in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L,a heavy chain CDR3 comprising the amino acid sequence of any one of theHCDR3s in SEQ ID NO: 399, SEQ ID NO: 405, SEQ ID NO: 411, SEQ ID NO:417, SEQ ID NO: 423, SEQ ID NO: 429, SEQ ID NO: 435, SEQ ID NO: 441, SEQID NO: 447, SEQ ID NO: 453, SEQ ID NO: 459, SEQ ID NO: 465, SEQ ID NO:471, SEQ ID NO: 477, SEQ ID NO: 483, SEQ ID NO: 489, SEQ ID NO: 495, SEQID NO: 501, SEQ ID NO: 507, SEQ ID NO: 513, SEQ ID NO: 519, SEQ ID NO:525, SEQ ID NO: 531, SEQ ID NO: 537, SEQ ID NO: 543, SEQ ID NO: 549, SEQID NO: 555, SEQ ID NO: 561, SEQ ID NO: 567, SEQ ID NO: 573, SEQ ID NO:579, SEQ ID NO: 585, SEQ ID NO: 591, SEQ ID NO: 597, SEQ ID NO: 603, SEQID NO: 609, SEQ ID NO: 615, SEQ ID NO: 621, SEQ ID NO: 627, SEQ ID NO:633, SEQ ID NO: 639, SEQ ID NO: 645, SEQ ID NO: 651, SEQ ID NO: 657, SEQID NO: 663, SEQ ID NO: 669, SEQ ID NO: 675, SEQ ID NO: 681, SEQ ID NO:687, SEQ ID NO: 693, SEQ ID NO: 699, SEQ ID NO: 705, SEQ ID NO: 711, SEQID NO: 717, SEQ ID NO: 723, SEQ ID NO: 729, SEQ ID NO: 735, SEQ ID NO:741, SEQ ID NO: 747, SEQ ID NO: 753, SEQ ID NO: 759, SEQ ID NO: 765, SEQID NO: 771, SEQ ID NO: 777, SEQ ID NO: 783, SEQ ID NO: 789, SEQ ID NO:795, SEQ ID NO: 801, SEQ ID NO: 807, SEQ ID NO: 813, SEQ ID NO: 819, SEQID NO: 825, SEQ ID NO: 831, SEQ ID NO: 837, SEQ ID NO: 843, SEQ ID NO:849, SEQ ID NO: 855, SEQ ID NO: 861, SEQ ID NO: 867, SEQ ID NO: 873, SEQID NO: 879, SEQ ID NO: 885, SEQ ID NO: 891, SEQ ID NO: 897, SEQ ID NO:903, SEQ ID NO: 909, SEQ ID NO: 915, SEQ ID NO: 921, SEQ ID NO: 927, SEQID NO: 933, SEQ ID NO: 939, SEQ ID NO: 945, SEQ ID NO: 951, SEQ ID NO:957, SEQ ID NO: 963, SEQ ID NO: 969, SEQ ID NO: 975, SEQ ID NO: 981, SEQID NO: 987, SEQ ID NO: 993, SEQ ID NO: 999, SEQ ID NO: 1005, SEQ ID NO:1011, SEQ ID NO: 1017, SEQ ID NO: 1023, SEQ ID NO: 1029, SEQ ID NO:1035, SEQ ID NO: 1041, SEQ ID NO: 1047, SEQ ID NO: 1053, SEQ ID NO:1059, SEQ ID NO: 1065, SEQ ID NO: 1071, SEQ ID NO: 1077, SEQ ID NO:1083, SEQ ID NO: 1089, SEQ ID NO: 1095, SEQ ID NO: 1101, SEQ ID NO:1107, SEQ ID NO: 1113, SEQ ID NO: 1119, SEQ ID NO: 1125, SEQ ID NO:1131, SEQ ID NO: 1137, SEQ ID NO: 1143, SEQ ID NO: 1149, SEQ ID NO:1155, SEQ ID NO: 1161, SEQ ID NO: 1167, SEQ ID NO: 1173, SEQ ID NO:1179, SEQ ID NO: 1185, SEQ ID NO: 1191, SEQ ID NO: 1197, SEQ ID NO:1203, SEQ ID NO: 1209, SEQ ID NO: 1215, SEQ ID NO: 1221, SEQ ID NO:1227, SEQ ID NO: 1233, SEQ ID NO: 1239, SEQ ID NO: 1245, SEQ ID NO:1251, SEQ ID NO: 1257, SEQ ID NO: 1263, SEQ ID NO: 1269, SEQ ID NO:1275, SEQ ID NO: 1281, SEQ ID NO: 1287, SEQ ID NO: 1293, SEQ ID NO:1299, SEQ ID NO: 1305, SEQ ID NO: 1311, SEQ ID NO: 1317, SEQ ID NO:1323, SEQ ID NO: 1329, SEQ ID NO: 1335, SEQ ID NO: 1341, SEQ ID NO:1347, SEQ ID NO: 1353, SEQ ID NO: 1359, SEQ ID NO: 1365, SEQ ID NO:1371, SEQ ID NO: 1377, SEQ ID NO: 1383, SEQ ID NO: 1389, SEQ ID NO:1395, SEQ ID NO: 1401, SEQ ID NO: 1407, SEQ ID NO: 1413, SEQ ID NO:1419, SEQ ID NO: 1425, SEQ ID NO: 1431, SEQ ID NO: 1437, SEQ ID NO:1443, SEQ ID NO: 1449, SEQ ID NO: 1455, SEQ ID NO: 1461, SEQ ID NO:1467, SEQ ID NO: 1473, SEQ ID NO: 1479, SEQ ID NO: 1485, SEQ ID NO:1491, SEQ ID NO: 1497, SEQ ID NO: 1503, SEQ ID NO: 1509, SEQ ID NO:1515, SEQ ID NO: 1521, SEQ ID NO: 1595, SEQ ID NO: 1527, SEQ ID NO:1533, SEQ ID NO: 1539, SEQ ID NO: 1545, SEQ ID NO: 1551, SEQ ID NO:1557, SEQ ID NO: 1563, SEQ ID NO: 1569, SEQ ID NO: 1575, SEQ ID NO:1581, or SEQ ID NO: 1587 as shown in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G,3H, 3I, 3J, 3K, or 3L, a light chain CDR1 comprising the amino acidsequence of any one of the LCDR1s in SEQ ID NO: 400, SEQ ID NO: 406, SEQID NO: 412, SEQ ID NO: 418, SEQ ID NO: 424, SEQ ID NO: 430, SEQ ID NO:436, SEQ ID NO: 442, SEQ ID NO: 448, SEQ ID NO: 454, SEQ ID NO: 460, SEQID NO: 466, SEQ ID NO: 472, SEQ ID NO: 478, SEQ ID NO: 484, SEQ ID NO:490, SEQ ID NO: 496, SEQ ID NO: 502, SEQ ID NO: 508, SEQ ID NO: 514, SEQID NO: 520, SEQ ID NO: 526, SEQ ID NO: 532, SEQ ID NO: 538, SEQ ID NO:544, SEQ ID NO: 550, SEQ ID NO: 556, SEQ ID NO: 562, SEQ ID NO: 568, SEQID NO: 574, SEQ ID NO: 580, SEQ ID NO: 586, SEQ ID NO: 592, SEQ ID NO:598, SEQ ID NO: 604, SEQ ID NO: 610, SEQ ID NO: 616, SEQ ID NO: 622, SEQID NO: 628, SEQ ID NO: 634, SEQ ID NO: 640, SEQ ID NO: 646, SEQ ID NO:652, SEQ ID NO: 658, SEQ ID NO: 664, SEQ ID NO: 670, SEQ ID NO: 676, SEQID NO: 682, SEQ ID NO: 688, SEQ ID NO: 694, SEQ ID NO: 700, SEQ ID NO:706, SEQ ID NO: 712, SEQ ID NO: 718, SEQ ID NO: 724, SEQ ID NO: 730, SEQID NO: 736, SEQ ID NO: 742, SEQ ID NO: 748, SEQ ID NO: 754, SEQ ID NO:760, SEQ ID NO: 766, SEQ ID NO: 772, SEQ ID NO: 778, SEQ ID NO: 784, SEQID NO: 790, SEQ ID NO: 796, SEQ ID NO: 802, SEQ ID NO: 808, SEQ ID NO:814, SEQ ID NO: 820, SEQ ID NO: 826, SEQ ID NO: 832, SEQ ID NO: 838, SEQID NO: 844, SEQ ID NO: 850, SEQ ID NO: 856, SEQ ID NO: 862, SEQ ID NO:868, SEQ ID NO: 874, SEQ ID NO: 880, SEQ ID NO: 886, SEQ ID NO: 892, SEQID NO: 898, SEQ ID NO: 904, SEQ ID NO: 910, SEQ ID NO: 916, SEQ ID NO:922, SEQ ID NO: 928, SEQ ID NO: 934, SEQ ID NO: 940, SEQ ID NO: 946, SEQID NO: 952, SEQ ID NO: 958, SEQ ID NO: 964, SEQ ID NO: 970, SEQ ID NO:976, SEQ ID NO: 982, SEQ ID NO: 988, SEQ ID NO: 994, SEQ ID NO: 1000,SEQ ID NO: 1006, SEQ ID NO: 1012, SEQ ID NO: 1018, SEQ ID NO: 1024, SEQID NO: 1030, SEQ ID NO: 1036, SEQ ID NO: 1042, SEQ ID NO: 1048, SEQ IDNO: 1054, SEQ ID NO: 1060, SEQ ID NO: 1066, SEQ ID NO: 1072, SEQ ID NO:1078, SEQ ID NO: 1084, SEQ ID NO: 1090, SEQ ID NO: 1096, SEQ ID NO:1102, SEQ ID NO: 1108, SEQ ID NO: 1114, SEQ ID NO: 1120, SEQ ID NO:1126, SEQ ID NO: 1132, SEQ ID NO: 1138, SEQ ID NO: 1144, SEQ ID NO:1150, SEQ ID NO: 1156, SEQ ID NO: 1162, SEQ ID NO: 1168, SEQ ID NO:1174, SEQ ID NO: 1180, SEQ ID NO: 1186, SEQ ID NO: 1192, SEQ ID NO:1198, SEQ ID NO: 1204, SEQ ID NO: 1210, SEQ ID NO: 1216, SEQ ID NO:1222, SEQ ID NO: 1228, SEQ ID NO: 1234, SEQ ID NO: 1240, SEQ ID NO:1246, SEQ ID NO: 1252, SEQ ID NO: 1258, SEQ ID NO: 1264, SEQ ID NO:1270, SEQ ID NO: 1276, SEQ ID NO: 1282, SEQ ID NO: 1288, SEQ ID NO:1294, SEQ ID NO: 1300, SEQ ID NO: 1306, SEQ ID NO: 1312, SEQ ID NO:1318, SEQ ID NO: 1324, SEQ ID NO: 1330, SEQ ID NO: 1336, SEQ ID NO:1342, SEQ ID NO: 1348, SEQ ID NO: 1354, SEQ ID NO: 1360, SEQ ID NO:1366, SEQ ID NO: 1372, SEQ ID NO: 1378, SEQ ID NO: 1384, SEQ ID NO:1390, SEQ ID NO: 1396, SEQ ID NO: 1402, SEQ ID NO: 1408, SEQ ID NO:1414, SEQ ID NO: 1420, SEQ ID NO: 1426, SEQ ID NO: 1432, SEQ ID NO:1438, SEQ ID NO: 1444, SEQ ID NO: 1450. SEQ ID NO: 1456, SEQ ID NO:1462, SEQ ID NO: 1468, SEQ ID NO: 1474, SEQ ID NO: 1480, SEQ ID NO:1486, SEQ ID NO: 1492, SEQ ID NO: 1498, SEQ ID NO: 1504, SEQ ID NO:1510, SEQ ID NO: 1516, SEQ ID NO: 1522, SEQ ID NO: 1596, SEQ ID NO:1528, SEQ ID NO: 1534, SEQ ID NO: 1540, SEQ ID NO: 1546, SEQ ID NO:1552, SEQ ID NO: 1558, SEQ ID NO: 1564, SEQ ID NO: 1570, SEQ ID NO:1576, SEQ ID NO: 1582, or SEQ ID NO: 1588 as shown in FIG. 3A, 3B, 3C,3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, a light chain CDR2 comprising theamino acid sequence of any one of the LCDR2s in SEQ ID NO: 401, SEQ IDNO: 407, SEQ ID NO: 413, SEQ ID NO: 419, SEQ ID NO: 425, SEQ ID NO: 431,SEQ ID NO: 437, SEQ ID NO: 443, SEQ ID NO: 449, SEQ ID NO: 455, SEQ IDNO: 461, SEQ ID NO: 467, SEQ ID NO: 473, SEQ ID NO: 479, SEQ ID NO: 485,SEQ ID NO: 491, SEQ ID NO: 497, SEQ ID NO: 503, SEQ ID NO: 509, SEQ IDNO: 515, SEQ ID NO: 521, SEQ ID NO: 527, SEQ ID NO: 533, SEQ ID NO: 539,SEQ ID NO: 545, SEQ ID NO: 551, SEQ ID NO: 557, SEQ ID NO: 563, SEQ IDNO: 569, SEQ ID NO: 575, SEQ ID NO: 581, SEQ ID NO: 587, SEQ ID NO: 593,SEQ ID NO: 599, SEQ ID NO: 605, SEQ ID NO: 611, SEQ ID NO: 617, SEQ IDNO: 623, SEQ ID NO: 629, SEQ ID NO: 635, SEQ ID NO: 641, SEQ ID NO: 647,SEQ ID NO: 653, SEQ ID NO: 659, SEQ ID NO: 665, SEQ ID NO: 671, SEQ IDNO: 677, SEQ ID NO: 683, SEQ ID NO: 689, SEQ ID NO: 695, SEQ ID NO: 701,SEQ ID NO: 707, SEQ ID NO: 713, SEQ ID NO: 719, SEQ ID NO: 725, SEQ IDNO: 731, SEQ ID NO: 737, SEQ ID NO: 743, SEQ ID NO: 749, SEQ ID NO: 755,SEQ ID NO: 761, SEQ ID NO: 767, SEQ ID NO: 773, SEQ ID NO: 779, SEQ IDNO: 785, SEQ ID NO: 791, SEQ ID NO: 797, SEQ ID NO: 803, SEQ ID NO: 809,SEQ ID NO: 815, SEQ ID NO: 821, SEQ ID NO: 827, SEQ ID NO: 833, SEQ IDNO: 839, SEQ ID NO: 845, SEQ ID NO: 851, SEQ ID NO: 857, SEQ ID NO: 863,SEQ ID NO: 869, SEQ ID NO: 875, SEQ ID NO: 881, SEQ ID NO: 887, SEQ IDNO: 893, SEQ ID NO: 899, SEQ ID NO: 905, SEQ ID NO: 911, SEQ ID NO: 917,SEQ ID NO: 923, SEQ ID NO: 929, SEQ ID NO: 935, SEQ ID NO: 941, SEQ IDNO: 947, SEQ ID NO: 953, SEQ ID NO: 959, SEQ ID NO: 965, SEQ ID NO: 971,SEQ ID NO: 977, SEQ ID NO: 983, SEQ ID NO: 989, SEQ ID NO: 995, SEQ IDNO: 1001, SEQ ID NO: 1007, SEQ ID NO: 1013, SEQ ID NO: 1019, SEQ ID NO:1025, SEQ ID NO: 1031, SEQ ID NO: 1037, SEQ ID NO: 1043, SEQ ID NO:1049, SEQ ID NO: 1055, SEQ ID NO: 1061, SEQ ID NO: 1067, SEQ ID NO:1073, SEQ ID NO: 1079, SEQ ID NO: 1085, SEQ ID NO: 1091, SEQ ID NO:1097, SEQ ID NO: 1103, SEQ ID NO: 1109, SEQ ID NO: 1115, SEQ ID NO:1121, SEQ ID NO: 1127, SEQ ID NO: 1133, SEQ ID NO: 1139, SEQ ID NO:1145, SEQ ID NO: 1151, SEQ ID NO: 1157, SEQ ID NO: 1163, SEQ ID NO:1169, SEQ ID NO: 1175, SEQ ID NO: 1181, SEQ ID NO: 1187, SEQ ID NO:1193, SEQ ID NO: 1199, SEQ ID NO: 1205, SEQ ID NO: 1211, SEQ ID NO:1217, SEQ ID NO: 1223, SEQ ID NO: 1229, SEQ ID NO: 1235, SEQ ID NO:1241, SEQ ID NO: 1247, SEQ ID NO: 1253, SEQ ID NO: 1259, SEQ ID NO:1265, SEQ ID NO: 1271, SEQ ID NO: 1277, SEQ ID NO: 1283, SEQ ID NO:1289, SEQ ID NO: 1295, SEQ ID NO: 1301, SEQ ID NO: 1307, SEQ ID NO:1313, SEQ ID NO: 1319, SEQ ID NO: 1325, SEQ ID NO: 1331, SEQ ID NO:1337, SEQ ID NO: 1343, SEQ ID NO: 1349, SEQ ID NO: 1355, SEQ ID NO:1361, SEQ ID NO: 1367, SEQ ID NO: 1373, SEQ ID NO: 1379, SEQ ID NO:1385, SEQ ID NO: 1391, SEQ ID NO: 1397, SEQ ID NO: 1403, SEQ ID NO:1409, SEQ ID NO: 1415, SEQ ID NO: 1421, SEQ ID NO: 1427, SEQ ID NO:1433, SEQ ID NO: 1439, SEQ ID NO: 1445, SEQ ID NO: 1451, SEQ ID NO:1457, SEQ ID NO: 1463, SEQ ID NO: 1469, SEQ ID NO: 1475, SEQ ID NO:1481, SEQ ID NO: 1487, SEQ ID NO: 1493, SEQ ID NO: 1499, SEQ ID NO:1505, SEQ ID NO: 1511, SEQ ID NO: 1517, SEQ ID NO: 1523, SEQ ID NO:1597, SEQ ID NO: 1529, SEQ ID NO: 1535, SEQ ID NO: 1541, SEQ ID NO:1547, SEQ ID NO: 1553, SEQ ID NO: 1559, SEQ ID NO: 1565, SEQ ID NO:1571, SEQ ID NO: 1577, SEQ ID NO: 1583, or SEQ ID NO: 1589 as shown inFIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, and a lightchain CDR3 comprising the amino acid sequence of any one of the LCDR3sin SEQ ID NO: 402, SEQ ID NO: 408, SEQ ID NO: 414, SEQ ID NO: 420, SEQID NO: 426, SEQ ID NO: 432, SEQ ID NO: 438, SEQ ID NO: 444, SEQ ID NO:450, SEQ ID NO: 456, SEQ ID NO: 462, SEQ ID NO: 468, SEQ ID NO: 474, SEQID NO: 480, SEQ ID NO: 486, SEQ ID NO: 492, SEQ ID NO: 498, SEQ ID NO:504, SEQ ID NO: 510, SEQ ID NO: 516, SEQ ID NO: 522, SEQ ID NO: 528, SEQID NO: 534, SEQ ID NO: 540, SEQ ID NO: 546, SEQ ID NO: 552, SEQ ID NO:558, SEQ ID NO: 564, SEQ ID NO: 570, SEQ ID NO: 576, SEQ ID NO: 582, SEQID NO: 588, SEQ ID NO: 594, SEQ ID NO: 600, SEQ ID NO: 606, SEQ ID NO:612, SEQ ID NO: 618, SEQ ID NO: 624, SEQ ID NO: 630, SEQ ID NO: 636, SEQID NO: 642, SEQ ID NO: 648, SEQ ID NO: 654, SEQ ID NO: 660, SEQ ID NO:666, SEQ ID NO: 672, SEQ ID NO: 678, SEQ ID NO: 684, SEQ ID NO: 690, SEQID NO: 696, SEQ ID NO: 702, SEQ ID NO: 708, SEQ ID NO: 714, SEQ ID NO:720, SEQ ID NO: 726, SEQ ID NO: 732, SEQ ID NO: 738, SEQ ID NO: 744, SEQID NO: 750, SEQ ID NO: 756, SEQ ID NO: 762, SEQ ID NO: 768, SEQ ID NO:774, SEQ ID NO: 780, SEQ ID NO: 786, SEQ ID NO: 792, SEQ ID NO: 798, SEQID NO: 804, SEQ ID NO: 810, SEQ ID NO: 816, SEQ ID NO: 822, SEQ ID NO:828, SEQ ID NO: 834, SEQ ID NO: 840, SEQ ID NO: 846, SEQ ID NO: 852, SEQID NO: 858, SEQ ID NO: 864, SEQ ID NO: 870, SEQ ID NO: 876, SEQ ID NO:882, SEQ ID NO: 888, SEQ ID NO: 894, SEQ ID NO: 900, SEQ ID NO: 906, SEQID NO: 912, SEQ ID NO: 918, SEQ ID NO: 924, SEQ ID NO: 930, SEQ ID NO:936, SEQ ID NO: 942, SEQ ID NO: 948, SEQ ID NO: 954, SEQ ID NO: 960, SEQID NO: 966, SEQ ID NO: 972, SEQ ID NO: 978, SEQ ID NO: 984, SEQ ID NO:990, SEQ ID NO: 996, SEQ ID NO: 1002, SEQ ID NO: 1008, SEQ ID NO: 1014,SEQ ID NO: 1020, SEQ ID NO: 1026, SEQ ID NO: 1032, SEQ ID NO: 1038, SEQID NO: 1044, SEQ ID NO: 1050, SEQ ID NO: 1056, SEQ ID NO: 1062, SEQ IDNO: 1068, SEQ ID NO: 1074, SEQ ID NO: 1080, SEQ ID NO: 1086, SEQ ID NO:1092, SEQ ID NO: 1098, SEQ ID NO: 1104, SEQ ID NO: 1110, SEQ ID NO:1116, SEQ ID NO: 1122, SEQ ID NO: 1128, SEQ ID NO: 1134, SEQ ID NO:1140, SEQ ID NO: 1146, SEQ ID NO: 1152, SEQ ID NO: 1158, SEQ ID NO:1164, SEQ ID NO: 1170, SEQ ID NO: 1176, SEQ ID NO: 1182, SEQ ID NO:1188, SEQ ID NO: 1194, SEQ ID NO: 1200, SEQ ID NO: 1206, SEQ ID NO:1212, SEQ ID NO: 1218, SEQ ID NO: 1224, SEQ ID NO: 1230, SEQ ID NO:1236, SEQ ID NO: 1242, SEQ ID NO: 1248, SEQ ID NO: 1254, SEQ ID NO:1260, SEQ ID NO: 1266, SEQ ID NO: 1272, SEQ ID NO: 1278, SEQ ID NO:1284, SEQ ID NO: 1290, SEQ ID NO: 1296, SEQ ID NO: 1302, SEQ ID NO:1308, SEQ ID NO: 1314, SEQ ID NO: 1320, SEQ ID NO: 1326, SEQ ID NO:1332, SEQ ID NO: 1338, SEQ ID NO: 1344, SEQ ID NO: 1350, SEQ ID NO:1356, SEQ ID NO: 1362, SEQ ID NO: 1368, SEQ ID NO: 1374, SEQ ID NO:1380, SEQ ID NO: 1386, SEQ ID NO: 1392, SEQ ID NO: 1398, SEQ ID NO:1404, SEQ ID NO: 1410, SEQ ID NO: 1416, SEQ ID NO: 1422, SEQ ID NO:1428, SEQ ID NO: 1434, SEQ ID NO: 1440, SEQ ID NO: 1446, SEQ ID NO:1452, SEQ ID NO: 1458, SEQ ID NO: 1464, SEQ ID NO: 1470, SEQ ID NO:1476, SEQ ID NO: 1482, SEQ ID NO: 1488, SEQ ID NO: 1494, SEQ ID NO:1500, SEQ ID NO: 1506, SEQ ID NO: 1512, SEQ ID NO: 1518, SEQ ID NO:1524, SEQ ID NO: 1598, SEQ ID NO: 1530, SEQ ID NO: 1536, SEQ ID NO:1542, SEQ ID NO: 1548, SEQ ID NO: 1554, SEQ ID NO: 1560, SEQ ID NO:1566, SEQ ID NO: 1572, SEQ ID NO: 1578, SEQ ID NO: 1584, or SEQ ID NO:1590 in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L.

In some embodiments, an isolated antibody comprises a heavy chain CDR1comprising the amino acid sequence of any of one of the HCDR1s in SEQ IDNO: 397, SEQ ID NO: 403. SEQ ID NO: 409, SEQ ID NO: 415, SEQ ID NO: 421,SEQ ID NO: 427, SEQ ID NO: 433, SEQ ID NO: 439, SEQ ID NO: 445, SEQ IDNO: 451, SEQ ID NO: 457, SEQ ID NO: 463, SEQ ID NO: 469, SEQ ID NO: 475,SEQ ID NO: 481, SEQ ID NO: 487, SEQ ID NO: 493, SEQ ID NO: 499, SEQ IDNO: 505, SEQ ID NO: 511, SEQ ID NO: 517, SEQ ID NO: 523, SEQ ID NO: 529,SEQ ID NO: 535, SEQ ID NO: 541, SEQ ID NO: 547, SEQ ID NO: 553, SEQ IDNO: 559, SEQ ID NO: 565, SEQ ID NO: 571, SEQ ID NO: 577, SEQ ID NO: 583,SEQ ID NO: 589, SEQ ID NO: 595, SEQ ID NO: 601, SEQ ID NO: 607, SEQ IDNO: 613, SEQ ID NO: 619, SEQ ID NO: 625, SEQ ID NO: 631, SEQ ID NO: 637,SEQ ID NO: 643, SEQ ID NO: 649, SEQ ID NO: 655, SEQ ID NO: 661, SEQ IDNO: 667, SEQ ID NO: 673, SEQ ID NO: 679, SEQ ID NO: 685, SEQ ID NO: 691,SEQ ID NO: 697, SEQ ID NO: 703, SEQ ID NO: 709, SEQ ID NO: 715, SEQ IDNO: 721, SEQ ID NO: 727, SEQ ID NO: 733, SEQ ID NO: 739, SEQ ID NO: 745,SEQ ID NO: 751, SEQ ID NO: 757, SEQ ID NO: 763, SEQ ID NO: 769, SEQ IDNO: 775, SEQ ID NO: 781, SEQ ID NO: 787, SEQ ID NO: 793, SEQ ID NO: 799,SEQ ID NO: 805, SEQ ID NO: 811, SEQ ID NO: 817, SEQ ID NO: 823, SEQ IDNO: 829, SEQ ID NO: 835, SEQ ID NO: 841, SEQ ID NO: 847, SEQ ID NO: 853,SEQ ID NO: 859, SEQ ID NO: 865, SEQ ID NO: 871, SEQ ID NO: 877, SEQ IDNO: 883, SEQ ID NO: 889, SEQ ID NO: 895, SEQ ID NO: 901, SEQ ID NO: 907,SEQ ID NO: 913, SEQ ID NO: 919, SEQ ID NO: 925, SEQ ID NO: 931, SEQ IDNO: 937, SEQ ID NO: 943, SEQ ID NO: 949, SEQ ID NO: 955, SEQ ID NO: 961,SEQ ID NO: 967, SEQ ID NO: 973, SEQ ID NO: 979, SEQ ID NO: 985, SEQ IDNO: 991, SEQ ID NO: 997, SEQ ID NO: 1003, SEQ ID NO: 1009, SEQ ID NO:1015, SEQ ID NO: 1021, SEQ ID NO: 1027, SEQ ID NO: 1033, SEQ ID NO:1039, SEQ ID NO: 1045, SEQ ID NO: 1051, SEQ ID NO: 1057, SEQ ID NO:1063, SEQ ID NO: 1069, SEQ ID NO: 1075, SEQ ID NO: 1081, SEQ ID NO:1087, SEQ ID NO: 1093, SEQ ID NO: 1099, SEQ ID NO: 1105, SEQ ID NO:1111, SEQ ID NO: 1117, SEQ ID NO: 1123, SEQ ID NO: 1129, SEQ ID NO:1135, SEQ ID NO: 1141, SEQ ID NO: 1147, SEQ ID NO: 1153, SEQ ID NO:1159, SEQ ID NO: 1165, SEQ ID NO: 1171, SEQ ID NO: 1177, SEQ ID NO:1183, SEQ ID NO: 1189, SEQ ID NO: 1195, SEQ ID NO: 1201, SEQ ID NO:1207, SEQ ID NO: 1213, SEQ ID NO: 1219, SEQ ID NO: 1225, SEQ ID NO:1231, SEQ ID NO: 1237, SEQ ID NO: 1243, SEQ ID NO: 1249, SEQ ID NO:1255, SEQ ID NO: 1261, SEQ ID NO: 1267, SEQ ID NO: 1273, SEQ ID NO:1279, SEQ ID NO: 1285, SEQ ID NO: 1291, SEQ ID NO: 1297, SEQ ID NO:1303, SEQ ID NO: 1309, SEQ ID NO: 1315, SEQ ID NO: 1321, SEQ ID NO:1327, SEQ ID NO: 1333, SEQ ID NO: 1339, SEQ ID NO: 1345, SEQ ID NO:1351, SEQ ID NO: 1357, SEQ ID NO: 1363, SEQ ID NO: 1369, SEQ ID NO:1375, SEQ ID NO: 1381, SEQ ID NO: 1387, SEQ ID NO: 1393, SEQ ID NO:1399, SEQ ID NO: 1405, SEQ ID NO: 1411, SEQ ID NO: 1417, SEQ ID NO:1423, SEQ ID NO: 1429, SEQ ID NO: 1435, SEQ ID NO: 1441, SEQ ID NO:1447, SEQ ID NO: 1453, SEQ ID NO: 1459, SEQ ID NO: 1465, SEQ ID NO:1471, SEQ ID NO: 1477, SEQ ID NO: 1483, SEQ ID NO: 1489, SEQ ID NO:1495, SEQ ID NO: 1501, SEQ ID NO: 1507, SEQ ID NO: 1513, SEQ ID NO:1519, SEQ ID NO: 1593, SEQ ID NO: 1525 SEQ ID NO: 1531, SEQ ID NO: 1537,SEQ ID NO: 1543, SEQ ID NO: 1549, SEQ ID NO: 1555, SEQ ID NO: 1561, SEQID NO: 1567, SEQ ID NO: 1573, SEQ ID NO: 1579, or SEQ ID NO: 1585 asshown in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, a heavychain CDR2 comprising the amino acid sequence of any one of the HCDR2sin SEQ ID NO: 398, SEQ ID NO: 404, SEQ ID NO: 410, SEQ ID NO: 416, SEQID NO: 422, SEQ ID NO: 428, SEQ ID NO: 434, SEQ ID NO: 440, SEQ ID NO:446, SEQ ID NO: 452, SEQ ID NO: 458, SEQ ID NO: 464, SEQ ID NO: 470, SEQID NO: 476, SEQ ID NO: 482, SEQ ID NO: 488, SEQ ID NO: 494, SEQ ID NO:500, SEQ ID NO: 506, SEQ ID NO: 512, SEQ ID NO: 518, SEQ ID NO: 524, SEQID NO: 530, SEQ ID NO: 536, SEQ ID NO: 542, SEQ ID NO: 548, SEQ ID NO:554, SEQ ID NO: 560, SEQ ID NO: 566, SEQ ID NO: 572, SEQ ID NO: 578, SEQID NO: 584, SEQ ID NO: 590, SEQ ID NO: 596, SEQ ID NO: 602, SEQ ID NO:608, SEQ ID NO: 614, SEQ ID NO: 620, SEQ ID NO: 626, SEQ ID NO: 632, SEQID NO: 638, SEQ ID NO: 644, SEQ ID NO: 650, SEQ ID NO: 656, SEQ ID NO:662, SEQ ID NO: 668, SEQ ID NO: 674, SEQ ID NO: 680, SEQ ID NO: 686, SEQID NO: 692, SEQ ID NO: 698, SEQ ID NO: 704, SEQ ID NO: 710, SEQ ID NO:716, SEQ ID NO: 722, SEQ ID NO: 728, SEQ ID NO: 734, SEQ ID NO: 740, SEQID NO: 746, SEQ ID NO: 752, SEQ ID NO: 758, SEQ ID NO: 764, SEQ ID NO:770, SEQ ID NO: 776, SEQ ID NO: 782, SEQ ID NO: 788, SEQ ID NO: 794, SEQID NO: 800, SEQ ID NO: 806, SEQ ID NO: 812, SEQ ID NO: 818, SEQ ID NO:824, SEQ ID NO: 830, SEQ ID NO: 836, SEQ ID NO: 842, SEQ ID NO: 848, SEQID NO: 854, SEQ ID NO: 860, SEQ ID NO: 866, SEQ ID NO: 872, SEQ ID NO:878, SEQ ID NO: 884, SEQ ID NO: 890, SEQ ID NO: 896, SEQ ID NO: 902, SEQID NO: 908, SEQ ID NO: 914, SEQ ID NO: 920, SEQ ID NO: 926, SEQ ID NO:932, SEQ ID NO: 938, SEQ ID NO: 944, SEQ ID NO: 950, SEQ ID NO: 956, SEQID NO: 962, SEQ ID NO: 968, SEQ ID NO: 974, SEQ ID NO: 980, SEQ ID NO:986, SEQ ID NO: 992, SEQ ID NO: 998, SEQ ID NO: 1004, SEQ ID NO: 1010,SEQ ID NO: 1016, SEQ ID NO: 1022, SEQ ID NO: 1028, SEQ ID NO: 1034, SEQID NO: 1040, SEQ ID NO: 1046, SEQ ID NO: 1052, SEQ ID NO: 1058, SEQ IDNO: 1064, SEQ ID NO: 1070, SEQ ID NO: 1076, SEQ ID NO: 1082, SEQ ID NO:1088, SEQ ID NO: 1094, SEQ ID NO: 1100, SEQ ID NO: 1106, SEQ ID NO:1112, SEQ ID NO: 1118, SEQ ID NO: 1124, SEQ ID NO: 1130, SEQ ID NO:1136, SEQ ID NO: 1142, SEQ ID NO: 1148, SEQ ID NO: 1154, SEQ ID NO:1160, SEQ ID NO: 1166, SEQ ID NO: 1172, SEQ ID NO: 1178, SEQ ID NO:1184, SEQ ID NO: 1190, SEQ ID NO: 1196, SEQ ID NO: 1202, SEQ ID NO:1208, SEQ ID NO: 1214, SEQ ID NO: 1220, SEQ ID NO: 1226, SEQ ID NO:1232, SEQ ID NO: 1238, SEQ ID NO: 1244, SEQ ID NO: 1250, SEQ ID NO:1256, SEQ ID NO: 1262, SEQ ID NO: 1268, SEQ ID NO: 1274, SEQ ID NO:1280, SEQ ID NO: 1286, SEQ ID NO: 1292, SEQ ID NO: 1298, SEQ ID NO:1304, SEQ ID NO: 1310, SEQ ID NO: 1316, SEQ ID NO: 1322, SEQ ID NO:1328, SEQ ID NO: 1334, SEQ ID NO: 1340, SEQ ID NO: 1346, SEQ ID NO:1352, SEQ ID NO: 1358, SEQ ID NO: 1364, SEQ ID NO: 1370, SEQ ID NO:1376, SEQ ID NO: 1382, SEQ ID NO: 1388, SEQ ID NO: 1394, SEQ ID NO:1400, SEQ ID NO: 1406, SEQ ID NO: 1412, SEQ ID NO: 1418, SEQ ID NO:1424, SEQ ID NO: 1430, SEQ ID NO: 1436, SEQ ID NO: 1442, SEQ ID NO:1448, SEQ ID NO: 1454, SEQ ID NO: 1460, SEQ ID NO: 1466, SEQ ID NO:1472, SEQ ID NO: 1478, SEQ ID NO: 1484, SEQ ID NO: 1490, SEQ ID NO:1496, SEQ ID NO: 1502, SEQ ID NO: 1508, SEQ ID NO: 1514, SEQ ID NO:1520, SEQ ID NO: 1594, SEQ ID NO: 1526, SEQ ID NO: 1532, SEQ ID NO:1538, SEQ ID NO: 1544, SEQ ID NO: 1550, SEQ ID NO: 1556, SEQ ID NO:1562, SEQ ID NO: 1568, SEQ ID NO: 1574, SEQ ID NO: 1580, or SEQ ID NO:1586 as shown in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L,a heavy chain CDR3 comprising the amino acid sequence of any one of theHCDR3s in SEQ ID NO: 399, SEQ ID NO: 405, SEQ ID NO: 411, SEQ ID NO:417, SEQ ID NO: 423, SEQ ID NO: 429, SEQ ID NO: 435, SEQ ID NO: 441, SEQID NO: 447, SEQ ID NO: 453, SEQ ID NO: 459, SEQ ID NO: 465, SEQ ID NO:471, SEQ ID NO: 477, SEQ ID NO: 483, SEQ ID NO: 489, SEQ ID NO: 495, SEQID NO: 501, SEQ ID NO: 507, SEQ ID NO: 513, SEQ ID NO: 519, SEQ ID NO:525, SEQ ID NO: 531, SEQ ID NO: 537, SEQ ID NO: 543, SEQ ID NO: 549, SEQID NO: 555, SEQ ID NO: 561, SEQ ID NO: 567, SEQ ID NO: 573, SEQ ID NO:579, SEQ ID NO: 585, SEQ ID NO: 591, SEQ ID NO: 597, SEQ ID NO: 603, SEQID NO: 609, SEQ ID NO: 615, SEQ ID NO: 621, SEQ ID NO: 627, SEQ ID NO:633, SEQ ID NO: 639, SEQ ID NO: 645, SEQ ID NO: 651, SEQ ID NO: 657, SEQID NO: 663, SEQ ID NO: 669, SEQ ID NO: 675, SEQ ID NO: 681, SEQ ID NO:687, SEQ ID NO: 693, SEQ ID NO: 699, SEQ ID NO: 705, SEQ ID NO: 711, SEQID NO: 717, SEQ ID NO: 723, SEQ ID NO: 729, SEQ ID NO: 735, SEQ ID NO:741, SEQ ID NO: 747, SEQ ID NO: 753, SEQ ID NO: 759, SEQ ID NO: 765, SEQID NO: 771, SEQ ID NO: 777, SEQ ID NO: 783, SEQ ID NO: 789, SEQ ID NO:795, SEQ ID NO: 801, SEQ ID NO: 807, SEQ ID NO: 813, SEQ ID NO: 819, SEQID NO: 825, SEQ ID NO: 831, SEQ ID NO: 837, SEQ ID NO: 843, SEQ ID NO:849, SEQ ID NO: 855, SEQ ID NO: 861, SEQ ID NO: 867, SEQ ID NO: 873, SEQID NO: 879, SEQ ID NO: 885, SEQ ID NO: 891, SEQ ID NO: 897, SEQ ID NO:903, SEQ ID NO: 909, SEQ ID NO: 915, SEQ ID NO: 921, SEQ ID NO: 927, SEQID NO: 933, SEQ ID NO: 939, SEQ ID NO: 945, SEQ ID NO: 951, SEQ ID NO:957, SEQ ID NO: 963, SEQ ID NO: 969, SEQ ID NO: 975, SEQ ID NO: 981, SEQID NO: 987, SEQ ID NO: 993, SEQ ID NO: 999, SEQ ID NO: 1005, SEQ ID NO:1011, SEQ ID NO: 1017, SEQ ID NO: 1023, SEQ ID NO: 1029, SEQ ID NO:1035, SEQ ID NO: 1041, SEQ ID NO: 1047, SEQ ID NO: 1053, SEQ ID NO:1059, SEQ ID NO: 1065, SEQ ID NO: 1071, SEQ ID NO: 1077, SEQ ID NO:1083, SEQ ID NO: 1089, SEQ ID NO: 1095, SEQ ID NO: 1101, SEQ ID NO:1107, SEQ ID NO: 1113, SEQ ID NO: 1119, SEQ ID NO: 1125, SEQ ID NO:1131, SEQ ID NO: 1137, SEQ ID NO: 1143, SEQ ID NO: 1149, SEQ ID NO:1155, SEQ ID NO: 1161, SEQ ID NO: 1167, SEQ ID NO: 1173, SEQ ID NO:1179, SEQ ID NO: 1185, SEQ ID NO: 1191, SEQ ID NO: 1197, SEQ ID NO:1203, SEQ ID NO: 1209, SEQ ID NO: 1215, SEQ ID NO: 1221, SEQ ID NO:1227, SEQ ID NO: 1233, SEQ ID NO: 1239, SEQ ID NO: 1245, SEQ ID NO:1251, SEQ ID NO: 1257, SEQ ID NO: 1263, SEQ ID NO: 1269, SEQ ID NO:1275, SEQ ID NO: 1281, SEQ ID NO: 1287, SEQ ID NO: 1293, SEQ ID NO:1299, SEQ ID NO: 1305, SEQ ID NO: 1311, SEQ ID NO: 1317, SEQ ID NO:1323, SEQ ID NO: 1329, SEQ ID NO: 1335, SEQ ID NO: 1341, SEQ ID NO:1347, SEQ ID NO: 1353, SEQ ID NO: 1359, SEQ ID NO: 1365, SEQ ID NO:1371, SEQ ID NO: 1377, SEQ ID NO: 1383, SEQ ID NO: 1389, SEQ ID NO:1395, SEQ ID NO: 1401, SEQ ID NO: 1407, SEQ ID NO: 1413, SEQ ID NO:1419, SEQ ID NO: 1425, SEQ ID NO: 1431, SEQ ID NO: 1437, SEQ ID NO:1443, SEQ ID NO: 1449, SEQ ID NO: 1455, SEQ ID NO: 1461, SEQ ID NO:1467, SEQ ID NO: 1473, SEQ ID NO: 1479, SEQ ID NO: 1485, SEQ ID NO:1491, SEQ ID NO: 1497, SEQ ID NO: 1503, SEQ ID NO: 1509, SEQ ID NO:1515, SEQ ID NO: 1521, SEQ ID NO: 1595, SEQ ID NO: 1527, SEQ ID NO:1533, SEQ ID NO: 1539, SEQ ID NO: 1545, SEQ ID NO: 1551, SEQ ID NO:1557, SEQ ID NO: 1563, SEQ ID NO: 1569, SEQ ID NO: 1575, SEQ ID NO:1581, or SEQ ID NO: 1587 as shown in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G,3H, 3I, 3J, 3K, or 3L, a light chain CDR1 comprising the amino acidsequence of any one of the LCDR1s in SEQ ID NO: 400, SEQ ID NO: 406, SEQID NO: 412, SEQ ID NO: 418, SEQ ID NO: 424, SEQ ID NO: 430, SEQ ID NO:436, SEQ ID NO: 442, SEQ ID NO: 448, SEQ ID NO: 454, SEQ ID NO: 460, SEQID NO: 466, SEQ ID NO: 472, SEQ ID NO: 478, SEQ ID NO: 484, SEQ ID NO:490, SEQ ID NO: 496, SEQ ID NO: 502, SEQ ID NO: 508, SEQ ID NO: 514, SEQID NO: 520, SEQ ID NO: 526, SEQ ID NO: 532, SEQ ID NO: 538, SEQ ID NO:544, SEQ ID NO: 550, SEQ ID NO: 556, SEQ ID NO: 562, SEQ ID NO: 568, SEQID NO: 574, SEQ ID NO: 580, SEQ ID NO: 586, SEQ ID NO: 592, SEQ ID NO:598, SEQ ID NO: 604, SEQ ID NO: 610, SEQ ID NO: 616, SEQ ID NO: 622, SEQID NO: 628, SEQ ID NO: 634, SEQ ID NO: 640, SEQ ID NO: 646, SEQ ID NO:652, SEQ ID NO: 658, SEQ ID NO: 664, SEQ ID NO: 670, SEQ ID NO: 676, SEQID NO: 682, SEQ ID NO: 688, SEQ ID NO: 694, SEQ ID NO: 700, SEQ ID NO:706, SEQ ID NO: 712, SEQ ID NO: 718, SEQ ID NO: 724, SEQ ID NO: 730, SEQID NO: 736, SEQ ID NO: 742, SEQ ID NO: 748, SEQ ID NO: 754, SEQ ID NO:760, SEQ ID NO: 766, SEQ ID NO: 772, SEQ ID NO: 778, SEQ ID NO: 784, SEQID NO: 790, SEQ ID NO: 796, SEQ ID NO: 802, SEQ ID NO: 808, SEQ ID NO:814, SEQ ID NO: 820, SEQ ID NO: 826, SEQ ID NO: 832, SEQ ID NO: 838, SEQID NO: 844, SEQ ID NO: 850, SEQ ID NO: 856, SEQ ID NO: 862, SEQ ID NO:868, SEQ ID NO: 874, SEQ ID NO: 880, SEQ ID NO: 886, SEQ ID NO: 892, SEQID NO: 898, SEQ ID NO: 904, SEQ ID NO: 910, SEQ ID NO: 916, SEQ ID NO:922, SEQ ID NO: 928, SEQ ID NO: 934, SEQ ID NO: 940, SEQ ID NO: 946, SEQID NO: 952, SEQ ID NO: 958, SEQ ID NO: 964, SEQ ID NO: 970, SEQ ID NO:976, SEQ ID NO: 982, SEQ ID NO: 988, SEQ ID NO: 994, SEQ ID NO: 1000,SEQ ID NO: 1006, SEQ ID NO: 1012, SEQ ID NO: 1018, SEQ ID NO: 1024, SEQID NO: 1030, SEQ ID NO: 1036, SEQ ID NO: 1042, SEQ ID NO: 1048, SEQ IDNO: 1054, SEQ ID NO: 1060, SEQ ID NO: 1066, SEQ ID NO: 1072, SEQ ID NO:1078, SEQ ID NO: 1084, SEQ ID NO: 1090, SEQ ID NO: 1096, SEQ ID NO:1102, SEQ ID NO: 1108, SEQ ID NO: 1114, SEQ ID NO: 1120, SEQ ID NO:1126, SEQ ID NO: 1132, SEQ ID NO: 1138, SEQ ID NO: 1144, SEQ ID NO:1150, SEQ ID NO: 1156, SEQ ID NO: 1162, SEQ ID NO: 1168, SEQ ID NO:1174, SEQ ID NO: 1180, SEQ ID NO: 1186, SEQ ID NO: 1192, SEQ ID NO:1198, SEQ ID NO: 1204, SEQ ID NO: 1210, SEQ ID NO: 1216, SEQ ID NO:1222, SEQ ID NO: 1228, SEQ ID NO: 1234, SEQ ID NO: 1240, SEQ ID NO:1246, SEQ ID NO: 1252, SEQ ID NO: 1258, SEQ ID NO: 1264, SEQ ID NO:1270, SEQ ID NO: 1276, SEQ ID NO: 1282, SEQ ID NO: 1288, SEQ ID NO:1294, SEQ ID NO: 1300, SEQ ID NO: 1306, SEQ ID NO: 1312, SEQ ID NO:1318, SEQ ID NO: 1324, SEQ ID NO: 1330, SEQ ID NO: 1336, SEQ ID NO:1342, SEQ ID NO: 1348, SEQ ID NO: 1354, SEQ ID NO: 1360, SEQ ID NO:1366, SEQ ID NO: 1372, SEQ ID NO: 1378, SEQ ID NO: 1384, SEQ ID NO:1390, SEQ ID NO: 1396, SEQ ID NO: 1402, SEQ ID NO: 1408, SEQ ID NO:1414, SEQ ID NO: 1420, SEQ ID NO: 1426, SEQ ID NO: 1432, SEQ ID NO:1438, SEQ ID NO: 1444, SEQ ID NO: 1450. SEQ ID NO: 1456, SEQ ID NO:1462, SEQ ID NO: 1468, SEQ ID NO: 1474, SEQ ID NO: 1480, SEQ ID NO:1486, SEQ ID NO: 1492, SEQ ID NO: 1498, SEQ ID NO: 1504, SEQ ID NO:1510, SEQ ID NO: 1516, SEQ ID NO: 1522, SEQ ID NO: 1596, SEQ ID NO:1528, SEQ ID NO: 1534, SEQ ID NO: 1540, SEQ ID NO: 1546, SEQ ID NO:1552, SEQ ID NO: 1558, SEQ ID NO: 1564, SEQ ID NO: 1570, SEQ ID NO:1576, SEQ ID NO: 1582, or SEQ ID NO: 1588 as shown in FIG. 3A, 3B, 3C,3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, a light chain CDR2 comprising theamino acid sequence of any one of the LCDR2s in SEQ ID NO: 401, SEQ IDNO: 407, SEQ ID NO: 413, SEQ ID NO: 419, SEQ ID NO: 425, SEQ ID NO: 431,SEQ ID NO: 437, SEQ ID NO: 443, SEQ ID NO: 449, SEQ ID NO: 455, SEQ IDNO: 461, SEQ ID NO: 467, SEQ ID NO: 473, SEQ ID NO: 479, SEQ ID NO: 485,SEQ ID NO: 491, SEQ ID NO: 497, SEQ ID NO: 503, SEQ ID NO: 509, SEQ IDNO: 515, SEQ ID NO: 521, SEQ ID NO: 527, SEQ ID NO: 533, SEQ ID NO: 539,SEQ ID NO: 545, SEQ ID NO: 551, SEQ ID NO: 557, SEQ ID NO: 563, SEQ IDNO: 569, SEQ ID NO: 575, SEQ ID NO: 581, SEQ ID NO: 587, SEQ ID NO: 593,SEQ ID NO: 599, SEQ ID NO: 605, SEQ ID NO: 611, SEQ ID NO: 617, SEQ IDNO: 623, SEQ ID NO: 629, SEQ ID NO: 635, SEQ ID NO: 641, SEQ ID NO: 647,SEQ ID NO: 653, SEQ ID NO: 659, SEQ ID NO: 665, SEQ ID NO: 671, SEQ IDNO: 677, SEQ ID NO: 683, SEQ ID NO: 689, SEQ ID NO: 695, SEQ ID NO: 701,SEQ ID NO: 707, SEQ ID NO: 713, SEQ ID NO: 719, SEQ ID NO: 725, SEQ IDNO: 731, SEQ ID NO: 737, SEQ ID NO: 743, SEQ ID NO: 749, SEQ ID NO: 755,SEQ ID NO: 761, SEQ ID NO: 767, SEQ ID NO: 773, SEQ ID NO: 779, SEQ IDNO: 785, SEQ ID NO: 791, SEQ ID NO: 797, SEQ ID NO: 803, SEQ ID NO: 809,SEQ ID NO: 815, SEQ ID NO: 821, SEQ ID NO: 827, SEQ ID NO: 833, SEQ IDNO: 839, SEQ ID NO: 845, SEQ ID NO: 851, SEQ ID NO: 857, SEQ ID NO: 863,SEQ ID NO: 869, SEQ ID NO: 875, SEQ ID NO: 881, SEQ ID NO: 887, SEQ IDNO: 893, SEQ ID NO: 899, SEQ ID NO: 905, SEQ ID NO: 911, SEQ ID NO: 917,SEQ ID NO: 923, SEQ ID NO: 929, SEQ ID NO: 935, SEQ ID NO: 941, SEQ IDNO: 947, SEQ ID NO: 953, SEQ ID NO: 959, SEQ ID NO: 965, SEQ ID NO: 971,SEQ ID NO: 977, SEQ ID NO: 983, SEQ ID NO: 989, SEQ ID NO: 995, SEQ IDNO: 1001, SEQ ID NO: 1007, SEQ ID NO: 1013, SEQ ID NO: 1019, SEQ ID NO:1025, SEQ ID NO: 1031, SEQ ID NO: 1037, SEQ ID NO: 1043, SEQ ID NO:1049, SEQ ID NO: 1055, SEQ ID NO: 1061, SEQ ID NO: 1067, SEQ ID NO:1073, SEQ ID NO: 1079, SEQ ID NO: 1085, SEQ ID NO: 1091, SEQ ID NO:1097, SEQ ID NO: 1103, SEQ ID NO: 1109, SEQ ID NO: 1115, SEQ ID NO:1121, SEQ ID NO: 1127, SEQ ID NO: 1133, SEQ ID NO: 1139, SEQ ID NO:1145, SEQ ID NO: 1151, SEQ ID NO: 1157, SEQ ID NO: 1163, SEQ ID NO:1169, SEQ ID NO: 1175, SEQ ID NO: 1181, SEQ ID NO: 1187, SEQ ID NO:1193, SEQ ID NO: 1199, SEQ ID NO: 1205, SEQ ID NO: 1211, SEQ ID NO:1217, SEQ ID NO: 1223, SEQ ID NO: 1229, SEQ ID NO: 1235, SEQ ID NO:1241, SEQ ID NO: 1247, SEQ ID NO: 1253, SEQ ID NO: 1259, SEQ ID NO:1265, SEQ ID NO: 1271, SEQ ID NO: 1277, SEQ ID NO: 1283, SEQ ID NO:1289, SEQ ID NO: 1295, SEQ ID NO: 1301, SEQ ID NO: 1307, SEQ ID NO:1313, SEQ ID NO: 1319, SEQ ID NO: 1325, SEQ ID NO: 1331, SEQ ID NO:1337, SEQ ID NO: 1343, SEQ ID NO: 1349, SEQ ID NO: 1355, SEQ ID NO:1361, SEQ ID NO: 1367, SEQ ID NO: 1373, SEQ ID NO: 1379, SEQ ID NO:1385, SEQ ID NO: 1391, SEQ ID NO: 1397, SEQ ID NO: 1403, SEQ ID NO:1409, SEQ ID NO: 1415, SEQ ID NO: 1421, SEQ ID NO: 1427, SEQ ID NO:1433, SEQ ID NO: 1439, SEQ ID NO: 1445, SEQ ID NO: 1451, SEQ ID NO:1457, SEQ ID NO: 1463, SEQ ID NO: 1469, SEQ ID NO: 1475, SEQ ID NO:1481, SEQ ID NO: 1487, SEQ ID NO: 1493, SEQ ID NO: 1499, SEQ ID NO:1505, SEQ ID NO: 1511, SEQ ID NO: 1517, SEQ ID NO: 1523, SEQ ID NO:1597, SEQ ID NO: 1529, SEQ ID NO: 1535, SEQ ID NO: 1541, SEQ ID NO:1547, SEQ ID NO: 1553, SEQ ID NO: 1559, SEQ ID NO: 1565, SEQ ID NO:1571, SEQ ID NO: 1577, SEQ ID NO: 1583, or SEQ ID NO: 1589 as shown inFIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, and a lightchain CDR3 comprising the amino acid sequence of any one of the LCDR3sin SEQ ID NO: 402, SEQ ID NO: 408, SEQ ID NO: 414, SEQ ID NO: 420, SEQID NO: 426, SEQ ID NO: 432, SEQ ID NO: 438, SEQ ID NO: 444, SEQ ID NO:450, SEQ ID NO: 456, SEQ ID NO: 462, SEQ ID NO: 468, SEQ ID NO: 474, SEQID NO: 480, SEQ ID NO: 486, SEQ ID NO: 492, SEQ ID NO: 498, SEQ ID NO:504, SEQ ID NO: 510, SEQ ID NO: 516, SEQ ID NO: 522, SEQ ID NO: 528, SEQID NO: 534, SEQ ID NO: 540, SEQ ID NO: 546, SEQ ID NO: 552, SEQ ID NO:558, SEQ ID NO: 564, SEQ ID NO: 570, SEQ ID NO: 576, SEQ ID NO: 582, SEQID NO: 588, SEQ ID NO: 594, SEQ ID NO: 600, SEQ ID NO: 606, SEQ ID NO:612, SEQ ID NO: 618, SEQ ID NO: 624, SEQ ID NO: 630, SEQ ID NO: 636, SEQID NO: 642, SEQ ID NO: 648, SEQ ID NO: 654, SEQ ID NO: 660, SEQ ID NO:666, SEQ ID NO: 672, SEQ ID NO: 678, SEQ ID NO: 684, SEQ ID NO: 690, SEQID NO: 696, SEQ ID NO: 702, SEQ ID NO: 708, SEQ ID NO: 714, SEQ ID NO:720, SEQ ID NO: 726, SEQ ID NO: 732, SEQ ID NO: 738, SEQ ID NO: 744, SEQID NO: 750, SEQ ID NO: 756, SEQ ID NO: 762, SEQ ID NO: 768, SEQ ID NO:774, SEQ ID NO: 780, SEQ ID NO: 786, SEQ ID NO: 792, SEQ ID NO: 798, SEQID NO: 804, SEQ ID NO: 810, SEQ ID NO: 816, SEQ ID NO: 822, SEQ ID NO:828, SEQ ID NO: 834, SEQ ID NO: 840, SEQ ID NO: 846, SEQ ID NO: 852, SEQID NO: 858, SEQ ID NO: 864, SEQ ID NO: 870, SEQ ID NO: 876, SEQ ID NO:882, SEQ ID NO: 888, SEQ ID NO: 894, SEQ ID NO: 900, SEQ ID NO: 906, SEQID NO: 912, SEQ ID NO: 918, SEQ ID NO: 924, SEQ ID NO: 930, SEQ ID NO:936, SEQ ID NO: 942, SEQ ID NO: 948, SEQ ID NO: 954, SEQ ID NO: 960, SEQID NO: 966, SEQ ID NO: 972, SEQ ID NO: 978, SEQ ID NO: 984, SEQ ID NO:990, SEQ ID NO: 996, SEQ ID NO: 1002, SEQ ID NO: 1008, SEQ ID NO: 1014,SEQ ID NO: 1020, SEQ ID NO: 1026, SEQ ID NO: 1032, SEQ ID NO: 1038, SEQID NO: 1044, SEQ ID NO: 1050, SEQ ID NO: 1056, SEQ ID NO: 1062, SEQ IDNO: 1068, SEQ ID NO: 1074, SEQ ID NO: 1080, SEQ ID NO: 1086, SEQ ID NO:1092, SEQ ID NO: 1098, SEQ ID NO: 1104, SEQ ID NO: 1110, SEQ ID NO:1116, SEQ ID NO: 1122, SEQ ID NO: 1128, SEQ ID NO: 1134, SEQ ID NO:1140, SEQ ID NO: 1146, SEQ ID NO: 1152, SEQ ID NO: 1158, SEQ ID NO:1164, SEQ ID NO: 1170, SEQ ID NO: 1176, SEQ ID NO: 1182, SEQ ID NO:1188, SEQ ID NO: 1194, SEQ ID NO: 1200, SEQ ID NO: 1206, SEQ ID NO:1212, SEQ ID NO: 1218, SEQ ID NO: 1224, SEQ ID NO: 1230, SEQ ID NO:1236, SEQ ID NO: 1242, SEQ ID NO: 1248, SEQ ID NO: 1254, SEQ ID NO:1260, SEQ ID NO: 1266, SEQ ID NO: 1272, SEQ ID NO: 1278, SEQ ID NO:1284, SEQ ID NO: 1290, SEQ ID NO: 1296, SEQ ID NO: 1302, SEQ ID NO:1308, SEQ ID NO: 1314, SEQ ID NO: 1320, SEQ ID NO: 1326, SEQ ID NO:1332, SEQ ID NO: 1338, SEQ ID NO: 1344, SEQ ID NO: 1350, SEQ ID NO:1356, SEQ ID NO: 1362, SEQ ID NO: 1368, SEQ ID NO: 1374, SEQ ID NO:1380, SEQ ID NO: 1386, SEQ ID NO: 1392, SEQ ID NO: 1398, SEQ ID NO:1404, SEQ ID NO: 1410, SEQ ID NO: 1416, SEQ ID NO: 1422, SEQ ID NO:1428, SEQ ID NO: 1434, SEQ ID NO: 1440, SEQ ID NO: 1446, SEQ ID NO:1452, SEQ ID NO: 1458, SEQ ID NO: 1464, SEQ ID NO: 1470, SEQ ID NO:1476, SEQ ID NO: 1482, SEQ ID NO: 1488, SEQ ID NO: 1494, SEQ ID NO:1500, SEQ ID NO: 1506, SEQ ID NO: 1512, SEQ ID NO: 1518, SEQ ID NO:1524, SEQ ID NO: 1598, SEQ ID NO: 1530, SEQ ID NO: 1536, SEQ ID NO:1542, SEQ ID NO: 1548, SEQ ID NO: 1554, SEQ ID NO: 1560, SEQ ID NO:1566, SEQ ID NO: 1572, SEQ ID NO: 1578, SEQ ID NO: 1584, or SEQ ID NO:1590 in FIG. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 3I, 3J, 3K, or 3L, and theHCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are from a same clone.

In some embodiments, an isolated antibody comprises a heavy chaincomprising the heavy chain amino acid variable sequence in any one ofSEQ ID NO. 1-SEQ ID NO: 97, SEQ ID NO: 195-SEQ ID NO: 209, or SEQ ID NO:225-SEQ ID NO: 310 as shown in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I,2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R.

In some embodiments, an isolated antibody comprises a heavy chaincomprising the heavy chain amino acid variable sequence in any one ofSEQ ID NO. 1-SEQ ID NO: 97, SEQ ID NO: 195-SEQ ID NO: 209, or SEQ ID NO:225-SEQ ID NO: 310 as shown in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I,2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R, or a sequence at least 90%identical thereto.

In some embodiments, an isolated antibody comprises a heavy chaincomprising the heavy chain amino acid variable sequence in any one ofSEQ ID NO. 1-SEQ ID NO: 97, SEQ ID NO: 195-SEQ ID NO: 209, or SEQ ID NO:225-SEQ ID NO: 310 as shown in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I,2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R, or a sequence with about 90, 91,92, 93, 94, 95, 96, 97, 98, 99, 99.9% identity thereto, or a valuewithin a range defined by any two of the aforementioned values.

In some embodiments, an isolated antibody that comprises a light chaincomprising the light chain amino acid variable sequence in any one ofSEQ ID NO: 98-SEQ ID NO: 194, SEQ ID NO: 210-SEQ ID NO: 224, or SEQ IDNO: 311-SEQ ID NO: 396 as shown in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H,2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R.

In some embodiments, an isolated antibody that comprises a light chaincomprising the light chain amino acid variable sequence in any one ofSEQ ID NO: 98-SEQ ID NO: 194, SEQ ID NO: 210-SEQ ID NO: 224, or SEQ IDNO: 311-SEQ ID NO: 396 as shown in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H,2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R, or a sequence at least 90%identical thereto.

In some embodiments, an isolated antibody that comprises a light chaincomprising the light chain amino acid variable sequence in any one ofSEQ ID NO: 98-SEQ ID NO: 194, SEQ ID NO: 210-SEQ ID NO: 224, or SEQ IDNO: 311-SEQ ID NO: 396 as shown in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H,2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R, or a sequence with about 90,91, 92, 93, 94, 95, 96, 97, 98, 99, 99.9% identity thereto, or a valuewithin a range defined by any two of the aforementioned values.

In some embodiments, an isolated antibody comprises a heavy chaincomprising the heavy chain amino acid variable sequence in any one ofSEQ ID NO. 1-SEQ ID NO: 97, SEQ ID NO: 195-SEQ ID NO: 209, or SEQ ID NO:225-SEQ ID NO: 310 as shown in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I,2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R, and a light chain comprising thelight chain amino acid variable sequence in any one of SEQ ID NO: 98-SEQID NO: 194, SEQ ID NO: 210-SEQ ID NO: 224, or SEQ ID NO: 311-SEQ ID NO:396 as shown in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M,2N, 2O, 2P, 2Q or 2R.

In some embodiments, an isolated antibody comprises a heavy chaincomprising the heavy chain amino acid variable sequence in any one ofSEQ ID NO. 1-SEQ ID NO: 97, SEQ ID NO: 195-SEQ ID NO: 209, or SEQ ID NO:225-SEQ ID NO: 310 as shown in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I,2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R, or a sequence at least 90%identical thereto, and a light chain comprising the light chain aminoacid variable sequence in any one of SEQ ID NO: 98-SEQ ID NO: 194, SEQID NO: 210-SEQ ID NO: 224, or SEQ ID NO: 311-SEQ ID NO: 396 as shown inFIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Qor 2R or a sequence at least 90% identical thereto.

In some embodiments, an isolated antibody comprises a heavy chaincomprising the heavy chain amino acid variable sequence in any one ofSEQ ID NO. 1-SEQ ID NO: 97, SEQ ID NO: 195-SEQ ID NO: 209, or SEQ ID NO:225-SEQ ID NO: 310 as shown in FIG. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I,2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R, or a sequence with about 90, 91,92, 93, 94, 95, 96, 97, 98, 99, 99.9% identity thereto, or a valuewithin a range defined by any two of the aforementioned values, and alight chain comprising the light chain amino acid variable sequence inany one of SEQ ID NO: 98-SEQ ID NO: 194, SEQ ID NO: 210-SEQ ID NO: 224,or SEQ ID NO: 311-SEQ ID NO: 396 as shown in FIG. 2A, 2B, 2C, 2D, 2E,2F, 2G, 2H, 2I, 2J, 2K, 2L, 2M, 2N, 2O, 2P, 2Q or 2R, or a sequence withabout 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.9% identity thereto, ora value within a range defined by any two of the aforementioned values.

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain variable region comprising the heavychain of clone Ab117 (SEQ ID NO: 62) and a light chain variable regioncomprising the light chain of clone Ab117 (SEQ ID NO: 159).

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain variable region comprising the heavychain of clone Ab53 (SEQ ID NO: 199) and a light chain variable regioncomprising the light chain of clone Ab53 (SEQ ID NO: 214).

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain variable region comprising the heavychain of clone Ab40 (SEQ ID NO: 200) and a light chain variable regioncomprising the light chain of clone Ab40 (SEQ ID NO: 215).

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain variable region comprising the heavychain of clone Ab48 (SEQ ID NO: 203) and a light chain variable regioncomprising the light chain of clone Ab48 (SEQ ID NO: 218).

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain variable region comprising the heavychain of clone Ab1 (SEQ ID NO: 299) and a light chain variable regioncomprising the light chain of clone Ab1 (SEQ ID NO: 385).

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain variable region comprising the heavychain of clone Ab143 (SEQ ID NO: 279) and a light chain variable regioncomprising the light chain of clone Ab143 (SEQ ID NO: 365).

In some embodiments, an isolated antigen binding molecule that binds tohuman TIGIT comprises a heavy chain variable region comprising the heavychain of clone Ab117 (SEQ ID NO: 62) and a light chain variable regioncomprising the light chain of clone Ab117 (SEQ ID NO: 159), a heavychain variable region comprising the heavy chain of clone Ab53 (SEQ IDNO: 199) and a light chain variable region comprising the light chain ofclone Ab53 (SEQ ID NO: 214), a heavy chain variable region comprisingthe heavy chain of clone Ab40 (SEQ ID NO: 200) and a light chainvariable region comprising the light chain of clone Ab40 (SEQ ID NO:215), a heavy chain variable region comprising the heavy chain of cloneAb48 (SEQ ID NO: 203) and a light chain variable region comprising thelight chain of clone Ab48 (SEQ ID NO: 218), a heavy chain variableregion comprising the heavy chain of clone Ab1 (SEQ ID NO: 299) and alight chain variable region comprising the light chain of clone Ab1 (SEQID NO: 385), or a heavy chain variable region comprising the heavy chainof clone Ab143 (SEQ ID NO: 279) and a light chain variable regioncomprising the light chain of clone Ab143 (SEQ ID NO: 365).

All of the references cited herein, including patents, patentapplications, papers, text books, and the like, and the references citedtherein, to the extent that they are not already, are herebyincorporated herein by reference in their entirety. To the extent thatany of the definitions or terms provided in the references incorporatedby reference are inconsistent with the terms and discussion providedherein, the present terms and definitions control.

1. An isolated antigen binding molecule that binds to human TIGIT,wherein the isolated antigen binding molecule comprises a heavy chainvariable region complementarity determining region 1 (CDR1), CDR2 andCDR3, and a light chain variable region CDR1, CDR2 and CDR3, wherein:the heavy chain variable region CDR1 comprises SSYX₄MX₆ (SEQ ID NO:1600) wherein X₄ is A, G, or S and X₆ is H, N, or S; the heavy chainvariable region CDR2 comprises WVY₃Y₄IY₆Y₇Y₈Y₉Y₁₀Y₁₁Y₁₂Y₁₃ (SEQ ID NO:1601) wherein Y₃ is S or A Y₄ is G, N, S, Y, or A Y₆ is S, K, or N Y₇ isS, Y, or G Y₈ is N or S Y₉ is G, S, A, or T Y₁₀ is G or S Y₁₁ is S, N,or T Y₁₂ is T, K, S, or I Y₁₃ is S, Y, or G; and a heavy chain variableregion CDR3 comprising ARZ₃PYZ₆Z₇WZ₉D (SEQ ID NO:1602) wherein Z₃ is V,A, G, or E Z₆ is S, D, or G Z₇ is V or Y Z₉ is I, A, M, or L.
 2. Theisolated antigen binding molecule of claim 1, wherein the heavy chainvariable region CDR1 comprises the amino acid sequence of any one of SEQID NO: 397, SEQ ID NO:
 403. SEQ ID NO: 409, SEQ ID NO: 415, SEQ ID NO:421, SEQ ID NO: 427, SEQ ID NO: 433, SEQ ID NO: 439, SEQ ID NO: 445, SEQID NO: 451, SEQ ID NO: 457, SEQ ID NO: 463, SEQ ID NO: 469, SEQ ID NO:475, SEQ ID NO: 481, SEQ ID NO: 487, SEQ ID NO: 493, SEQ ID NO: 499, SEQID NO: 505, SEQ ID NO: 511, SEQ ID NO: 517, SEQ ID NO: 523, SEQ ID NO:529, SEQ ID NO: 535, SEQ ID NO: 541, SEQ ID NO: 547, SEQ ID NO: 553, SEQID NO: 559, SEQ ID NO: 565, SEQ ID NO: 571, SEQ ID NO: 577, SEQ ID NO:583, SEQ ID NO: 589, SEQ ID NO: 595, SEQ ID NO: 601, SEQ ID NO: 607, SEQID NO: 613, SEQ ID NO: 619, SEQ ID NO: 625, SEQ ID NO: 631, SEQ ID NO:637, SEQ ID NO: 643, SEQ ID NO: 649, SEQ ID NO: 655, SEQ ID NO: 661, SEQID NO: 667, SEQ ID NO: 673, SEQ ID NO: 679, SEQ ID NO: 685, SEQ ID NO:691, SEQ ID NO: 697, SEQ ID NO: 703, SEQ ID NO: 709, SEQ ID NO: 715, SEQID NO: 721, SEQ ID NO: 727, SEQ ID NO: 733, SEQ ID NO: 739, SEQ ID NO:745, SEQ ID NO: 751, SEQ ID NO: 757, SEQ ID NO: 763, SEQ ID NO: 769, SEQID NO: 775, SEQ ID NO: 781, SEQ ID NO: 787, SEQ ID NO: 793, SEQ ID NO:799, SEQ ID NO: 805, SEQ ID NO: 811, SEQ ID NO: 817, SEQ ID NO: 823, SEQID NO: 829, SEQ ID NO: 835, SEQ ID NO: 841, SEQ ID NO: 847, SEQ ID NO:853, SEQ ID NO: 859, SEQ ID NO: 865, SEQ ID NO: 871, SEQ ID NO: 877, SEQID NO: 883, SEQ ID NO: 889, SEQ ID NO: 895, SEQ ID NO: 901, SEQ ID NO:907, SEQ ID NO: 913, SEQ ID NO: 919, SEQ ID NO: 925, SEQ ID NO: 931, SEQID NO: 937, SEQ ID NO: 943, SEQ ID NO: 949, SEQ ID NO: 955, SEQ ID NO:961, SEQ ID NO: 967, SEQ ID NO: 973, SEQ ID NO: 979, SEQ ID NO: 985, SEQID NO: 991, SEQ ID NO: 997, SEQ ID NO: 1003, SEQ ID NO: 1009, SEQ ID NO:1015, SEQ ID NO: 1021, SEQ ID NO: 1027, SEQ ID NO: 1033, SEQ ID NO:1039, SEQ ID NO: 1045, SEQ ID NO: 1051, SEQ ID NO: 1057, SEQ ID NO:1063, SEQ ID NO: 1069, SEQ ID NO: 1075, SEQ ID NO: 1081, SEQ ID NO:1087, SEQ ID NO: 1093, SEQ ID NO: 1099, SEQ ID NO: 1105, SEQ ID NO:1111, SEQ ID NO: 1117, SEQ ID NO: 1123, SEQ ID NO: 1129, SEQ ID NO:1135, SEQ ID NO: 1141, SEQ ID NO: 1147, SEQ ID NO: 1153, SEQ ID NO:1159, SEQ ID NO: 1165, SEQ ID NO: 1171, SEQ ID NO: 1177, SEQ ID NO:1183, SEQ ID NO: 1189, SEQ ID NO: 1195, SEQ ID NO: 1201, SEQ ID NO:1207, SEQ ID NO: 1213, SEQ ID NO: 1219, SEQ ID NO: 1225, SEQ ID NO:1231, SEQ ID NO: 1237, SEQ ID NO: 1243, SEQ ID NO: 1249, SEQ ID NO:1255, SEQ ID NO: 1261, SEQ ID NO: 1267, SEQ ID NO: 1273, SEQ ID NO:1279, SEQ ID NO: 1285, SEQ ID NO: 1291, SEQ ID NO: 1297, SEQ ID NO:1303, SEQ ID NO: 1309, SEQ ID NO: 1315, SEQ ID NO: 1321, SEQ ID NO:1327, SEQ ID NO: 1333, SEQ ID NO: 1339, SEQ ID NO: 1345, SEQ ID NO:1351, SEQ ID NO: 1357, SEQ ID NO: 1363, SEQ ID NO: 1369, SEQ ID NO:1375, SEQ ID NO: 1381, SEQ ID NO: 1387, SEQ ID NO: 1393, SEQ ID NO:1399, SEQ ID NO: 1405, SEQ ID NO: 1411, SEQ ID NO: 1417, SEQ ID NO:1423, SEQ ID NO: 1429, SEQ ID NO: 1435, SEQ ID NO: 1441, SEQ ID NO:1447, SEQ ID NO: 1453, SEQ ID NO: 1459, SEQ ID NO: 1465, SEQ ID NO:1471, SEQ ID NO: 1477, SEQ ID NO: 1483, SEQ ID NO: 1489, SEQ ID NO:1495, SEQ ID NO: 1501, SEQ ID NO: 1507, SEQ ID NO: 1513, SEQ ID NO:1519, SEQ ID NO: 1593, SEQ ID NO: 1525 SEQ ID NO: 1531, SEQ ID NO: 1537,SEQ ID NO: 1543, SEQ ID NO: 1549, SEQ ID NO: 1555, SEQ ID NO: 1561, SEQID NO: 1567, SEQ ID NO: 1573, SEQ ID NO: 1579 and SEQ ID NO:
 1585. 3.The isolated antigen binding molecule of claim 1, wherein the heavychain variable region CDR2 comprises the amino acid sequence of any oneof SEQ ID NO: 398, SEQ ID NO: 404, SEQ ID NO: 410, SEQ ID NO: 416, SEQID NO: 422, SEQ ID NO: 428, SEQ ID NO: 434, SEQ ID NO: 440, SEQ ID NO:446, SEQ ID NO: 452, SEQ ID NO: 458, SEQ ID NO: 464, SEQ ID NO: 470, SEQID NO: 476, SEQ ID NO: 482, SEQ ID NO: 488, SEQ ID NO: 494, SEQ ID NO:500, SEQ ID NO: 506, SEQ ID NO: 512, SEQ ID NO: 518, SEQ ID NO: 524, SEQID NO: 530, SEQ ID NO: 536, SEQ ID NO: 542, SEQ ID NO: 548, SEQ ID NO:554, SEQ ID NO: 560, SEQ ID NO: 566, SEQ ID NO: 572, SEQ ID NO: 578, SEQID NO: 584, SEQ ID NO: 590, SEQ ID NO: 596, SEQ ID NO: 602, SEQ ID NO:608, SEQ ID NO: 614, SEQ ID NO: 620, SEQ ID NO: 626, SEQ ID NO: 632, SEQID NO: 638, SEQ ID NO: 644, SEQ ID NO: 650, SEQ ID NO: 656, SEQ ID NO:662, SEQ ID NO: 668, SEQ ID NO: 674, SEQ ID NO: 680, SEQ ID NO: 686, SEQID NO: 692, SEQ ID NO: 698, SEQ ID NO: 704, SEQ ID NO: 710, SEQ ID NO:716, SEQ ID NO: 722, SEQ ID NO: 728, SEQ ID NO: 734, SEQ ID NO: 740, SEQID NO: 746, SEQ ID NO: 752, SEQ ID NO: 758, SEQ ID NO: 764, SEQ ID NO:770, SEQ ID NO: 776, SEQ ID NO: 782, SEQ ID NO: 788, SEQ ID NO: 794, SEQID NO: 800, SEQ ID NO: 806, SEQ ID NO: 812, SEQ ID NO: 818, SEQ ID NO:824, SEQ ID NO: 830, SEQ ID NO: 836, SEQ ID NO: 842, SEQ ID NO: 848, SEQID NO: 854, SEQ ID NO: 860, SEQ ID NO: 866, SEQ ID NO: 872, SEQ ID NO:878, SEQ ID NO: 884, SEQ ID NO: 890, SEQ ID NO: 896, SEQ ID NO: 902, SEQID NO: 908, SEQ ID NO: 914, SEQ ID NO: 920, SEQ ID NO: 926, SEQ ID NO:932, SEQ ID NO: 938, SEQ ID NO: 944, SEQ ID NO: 950, SEQ ID NO: 956, SEQID NO: 962, SEQ ID NO: 968, SEQ ID NO: 974, SEQ ID NO: 980, SEQ ID NO:986, SEQ ID NO: 992, SEQ ID NO: 998, SEQ ID NO: 1004, SEQ ID NO: 1010,SEQ ID NO: 1016, SEQ ID NO: 1022, SEQ ID NO: 1028, SEQ ID NO: 1034, SEQID NO: 1040, SEQ ID NO: 1046, SEQ ID NO: 1052, SEQ ID NO: 1058, SEQ IDNO: 1064, SEQ ID NO: 1070, SEQ ID NO: 1076, SEQ ID NO: 1082, SEQ ID NO:1088, SEQ ID NO: 1094, SEQ ID NO: 1100, SEQ ID NO: 1106, SEQ ID NO:1112, SEQ ID NO: 1118, SEQ ID NO: 1124, SEQ ID NO: 1130, SEQ ID NO:1136, SEQ ID NO: 1142, SEQ ID NO: 1148, SEQ ID NO: 1154, SEQ ID NO:1160, SEQ ID NO: 1166, SEQ ID NO: 1172, SEQ ID NO: 1178, SEQ ID NO:1184, SEQ ID NO: 1190, SEQ ID NO: 1196, SEQ ID NO: 1202, SEQ ID NO:1208, SEQ ID NO: 1214, SEQ ID NO: 1220, SEQ ID NO: 1226, SEQ ID NO:1232, SEQ ID NO: 1238, SEQ ID NO: 1244, SEQ ID NO: 1250, SEQ ID NO:1256, SEQ ID NO: 1262, SEQ ID NO: 1268, SEQ ID NO: 1274, SEQ ID NO:1280, SEQ ID NO: 1286, SEQ ID NO: 1292, SEQ ID NO: 1298, SEQ ID NO:1304, SEQ ID NO: 1310, SEQ ID NO: 1316, SEQ ID NO: 1322, SEQ ID NO:1328, SEQ ID NO: 1334, SEQ ID NO: 1340, SEQ ID NO: 1346, SEQ ID NO:1352, SEQ ID NO: 1358, SEQ ID NO: 1364, SEQ ID NO: 1370, SEQ ID NO:1376, SEQ ID NO: 1382, SEQ ID NO: 1388, SEQ ID NO: 1394, SEQ ID NO:1400, SEQ ID NO: 1406, SEQ ID NO: 1412, SEQ ID NO: 1418, SEQ ID NO:1424, SEQ ID NO: 1430, SEQ ID NO: 1436, SEQ ID NO: 1442, SEQ ID NO:1448, SEQ ID NO: 1454, SEQ ID NO: 1460, SEQ ID NO: 1466, SEQ ID NO:1472, SEQ ID NO: 1478, SEQ ID NO: 1484, SEQ ID NO: 1490, SEQ ID NO:1496, SEQ ID NO: 1502, SEQ ID NO: 1508, SEQ ID NO: 1514, SEQ ID NO:1520, SEQ ID NO: 1594, SEQ ID NO: 1526, SEQ ID NO: 1532, SEQ ID NO:1538, SEQ ID NO: 1544, SEQ ID NO: 1550, SEQ ID NO: 1556, SEQ ID NO:1562, SEQ ID NO: 1568, SEQ ID NO: 1574, SEQ ID NO: 1580, and SEQ ID NO:1586
 4. The isolated antigen binding molecule of claim 1, wherein theheavy chain variable region CDR3 comprises the amino acid sequence ofany one of SEQ ID NO: 399, SEQ ID NO: 405, SEQ ID NO: 411, SEQ ID NO:417, SEQ ID NO: 423, SEQ ID NO: 429, SEQ ID NO: 435, SEQ ID NO: 441, SEQID NO: 447, SEQ ID NO: 453, SEQ ID NO: 459, SEQ ID NO: 465, SEQ ID NO:471, SEQ ID NO: 477, SEQ ID NO: 483, SEQ ID NO: 489, SEQ ID NO: 495, SEQID NO: 501, SEQ ID NO: 507, SEQ ID NO: 513, SEQ ID NO: 519, SEQ ID NO:525, SEQ ID NO: 531, SEQ ID NO: 537, SEQ ID NO: 543, SEQ ID NO: 549, SEQID NO: 555, SEQ ID NO: 561, SEQ ID NO: 567, SEQ ID NO: 573, SEQ ID NO:579, SEQ ID NO: 585, SEQ ID NO: 591, SEQ ID NO: 597, SEQ ID NO: 603, SEQID NO: 609, SEQ ID NO: 615, SEQ ID NO: 621, SEQ ID NO: 627, SEQ ID NO:633, SEQ ID NO: 639, SEQ ID NO: 645, SEQ ID NO: 651, SEQ ID NO: 657, SEQID NO: 663, SEQ ID NO: 669, SEQ ID NO: 675, SEQ ID NO: 681, SEQ ID NO:687, SEQ ID NO: 693, SEQ ID NO: 699, SEQ ID NO: 705, SEQ ID NO: 711, SEQID NO: 717, SEQ ID NO: 723, SEQ ID NO: 729, SEQ ID NO: 735, SEQ ID NO:741, SEQ ID NO: 747, SEQ ID NO: 753, SEQ ID NO: 759, SEQ ID NO: 765, SEQID NO: 771, SEQ ID NO: 777, SEQ ID NO: 783, SEQ ID NO: 789, SEQ ID NO:795, SEQ ID NO: 801, SEQ ID NO: 807, SEQ ID NO: 813, SEQ ID NO: 819, SEQID NO: 825, SEQ ID NO: 831, SEQ ID NO: 837, SEQ ID NO: 843, SEQ ID NO:849, SEQ ID NO: 855, SEQ ID NO: 861, SEQ ID NO: 867, SEQ ID NO: 873, SEQID NO: 879, SEQ ID NO: 885, SEQ ID NO: 891, SEQ ID NO: 897, SEQ ID NO:903, SEQ ID NO: 909, SEQ ID NO: 915, SEQ ID NO: 921, SEQ ID NO: 927, SEQID NO: 933, SEQ ID NO: 939, SEQ ID NO: 945, SEQ ID NO: 951, SEQ ID NO:957, SEQ ID NO: 963, SEQ ID NO: 969, SEQ ID NO: 975, SEQ ID NO: 981, SEQID NO: 987, SEQ ID NO: 993, SEQ ID NO: 999, SEQ ID NO: 1005, SEQ ID NO:1011, SEQ ID NO: 1017, SEQ ID NO: 1023, SEQ ID NO: 1029, SEQ ID NO:1035, SEQ ID NO: 1041, SEQ ID NO: 1047, SEQ ID NO: 1053, SEQ ID NO:1059, SEQ ID NO: 1065, SEQ ID NO: 1071, SEQ ID NO: 1077, SEQ ID NO:1083, SEQ ID NO: 1089, SEQ ID NO: 1095, SEQ ID NO: 1101, SEQ ID NO:1107, SEQ ID NO: 1113, SEQ ID NO: 1119, SEQ ID NO: 1125, SEQ ID NO:1131, SEQ ID NO: 1137, SEQ ID NO: 1143, SEQ ID NO: 1149, SEQ ID NO:1155, SEQ ID NO: 1161, SEQ ID NO: 1167, SEQ ID NO: 1173, SEQ ID NO:1179, SEQ ID NO: 1185, SEQ ID NO: 1191, SEQ ID NO: 1197, SEQ ID NO:1203, SEQ ID NO: 1209, SEQ ID NO: 1215, SEQ ID NO: 1221, SEQ ID NO:1227, SEQ ID NO: 1233, SEQ ID NO: 1239, SEQ ID NO: 1245, SEQ ID NO:1251, SEQ ID NO: 1257, SEQ ID NO: 1263, SEQ ID NO: 1269, SEQ ID NO:1275, SEQ ID NO: 1281, SEQ ID NO: 1287, SEQ ID NO: 1293, SEQ ID NO:1299, SEQ ID NO: 1305, SEQ ID NO: 1311, SEQ ID NO: 1317, SEQ ID NO:1323, SEQ ID NO: 1329, SEQ ID NO: 1335, SEQ ID NO: 1341, SEQ ID NO:1347, SEQ ID NO: 1353, SEQ ID NO: 1359, SEQ ID NO: 1365, SEQ ID NO:1371, SEQ ID NO: 1377, SEQ ID NO: 1383, SEQ ID NO: 1389, SEQ ID NO:1395, SEQ ID NO: 1401, SEQ ID NO: 1407, SEQ ID NO: 1413, SEQ ID NO:1419, SEQ ID NO: 1425, SEQ ID NO: 1431, SEQ ID NO: 1437, SEQ ID NO:1443, SEQ ID NO: 1449, SEQ ID NO: 1455, SEQ ID NO: 1461, SEQ ID NO:1467, SEQ ID NO: 1473, SEQ ID NO: 1479, SEQ ID NO: 1485, SEQ ID NO:1491, SEQ ID NO: 1497, SEQ ID NO: 1503, SEQ ID NO: 1509, SEQ ID NO:1515, SEQ ID NO: 1521, SEQ ID NO: 1595, SEQ ID NO: 1527, SEQ ID NO:1533, SEQ ID NO: 1539, SEQ ID NO: 1545, SEQ ID NO: 1551, SEQ ID NO:1557, SEQ ID NO: 1563, SEQ ID NO: 1569, SEQ ID NO: 1575, SEQ ID NO: 158and SEQ ID NO:
 1587. 5. The isolated antigen binding molecule of claim1, wherein the light chain variable region CDR1 comprises the amino acidsequence any one of SEQ ID NO: 400, SEQ ID NO: 406, SEQ ID NO: 412, SEQID NO: 418, SEQ ID NO: 424, SEQ ID NO: 430, SEQ ID NO: 436, SEQ ID NO:442, SEQ ID NO: 448, SEQ ID NO: 454, SEQ ID NO: 460, SEQ ID NO: 466, SEQID NO: 472, SEQ ID NO: 478, SEQ ID NO: 484, SEQ ID NO: 490, SEQ ID NO:496, SEQ ID NO: 502, SEQ ID NO: 508, SEQ ID NO: 514, SEQ ID NO: 520, SEQID NO: 526, SEQ ID NO: 532, SEQ ID NO: 538, SEQ ID NO: 544, SEQ ID NO:550, SEQ ID NO: 556, SEQ ID NO: 562, SEQ ID NO: 568, SEQ ID NO: 574, SEQID NO: 580, SEQ ID NO: 586, SEQ ID NO: 592, SEQ ID NO: 598, SEQ ID NO:604, SEQ ID NO: 610, SEQ ID NO: 616, SEQ ID NO: 622, SEQ ID NO: 628, SEQID NO: 634, SEQ ID NO: 640, SEQ ID NO: 646, SEQ ID NO: 652, SEQ ID NO:658, SEQ ID NO: 664, SEQ ID NO: 670, SEQ ID NO: 676, SEQ ID NO: 682, SEQID NO: 688, SEQ ID NO: 694, SEQ ID NO: 700, SEQ ID NO: 706, SEQ ID NO:712, SEQ ID NO: 718, SEQ ID NO: 724, SEQ ID NO: 730, SEQ ID NO: 736, SEQID NO: 742, SEQ ID NO: 748, SEQ ID NO: 754, SEQ ID NO: 760, SEQ ID NO:766, SEQ ID NO: 772, SEQ ID NO: 778, SEQ ID NO: 784, SEQ ID NO: 790, SEQID NO: 796, SEQ ID NO: 802, SEQ ID NO: 808, SEQ ID NO: 814, SEQ ID NO:820, SEQ ID NO: 826, SEQ ID NO: 832, SEQ ID NO: 838, SEQ ID NO: 844, SEQID NO: 850, SEQ ID NO: 856, SEQ ID NO: 862, SEQ ID NO: 868, SEQ ID NO:874, SEQ ID NO: 880, SEQ ID NO: 886, SEQ ID NO: 892, SEQ ID NO: 898, SEQID NO: 904, SEQ ID NO: 910, SEQ ID NO: 916, SEQ ID NO: 922, SEQ ID NO:928, SEQ ID NO: 934, SEQ ID NO: 940, SEQ ID NO: 946, SEQ ID NO: 952, SEQID NO: 958, SEQ ID NO: 964, SEQ ID NO: 970, SEQ ID NO: 976, SEQ ID NO:982, SEQ ID NO: 988, SEQ ID NO: 994, SEQ ID NO: 1000, SEQ ID NO: 1006,SEQ ID NO: 1012, SEQ ID NO: 1018, SEQ ID NO: 1024, SEQ ID NO: 1030, SEQID NO: 1036, SEQ ID NO: 1042, SEQ ID NO: 1048, SEQ ID NO: 1054, SEQ IDNO: 1060, SEQ ID NO: 1066, SEQ ID NO: 1072, SEQ ID NO: 1078, SEQ ID NO:1084, SEQ ID NO: 1090, SEQ ID NO: 1096, SEQ ID NO: 1102, SEQ ID NO:1108, SEQ ID NO: 1114, SEQ ID NO: 1120, SEQ ID NO: 1126, SEQ ID NO:1132, SEQ ID NO: 1138, SEQ ID NO: 1144, SEQ ID NO: 1150, SEQ ID NO:1156, SEQ ID NO: 1162, SEQ ID NO: 1168, SEQ ID NO: 1174, SEQ ID NO:1180, SEQ ID NO: 1186, SEQ ID NO: 1192, SEQ ID NO: 1198, SEQ ID NO:1204, SEQ ID NO: 1210, SEQ ID NO: 1216, SEQ ID NO: 1222, SEQ ID NO:1228, SEQ ID NO: 1234, SEQ ID NO: 1240, SEQ ID NO: 1246, SEQ ID NO:1252, SEQ ID NO: 1258, SEQ ID NO: 1264, SEQ ID NO: 1270, SEQ ID NO:1276, SEQ ID NO: 1282, SEQ ID NO: 1288, SEQ ID NO: 1294, SEQ ID NO:1300, SEQ ID NO: 1306, SEQ ID NO: 1312, SEQ ID NO: 1318, SEQ ID NO:1324, SEQ ID NO: 1330, SEQ ID NO: 1336, SEQ ID NO: 1342, SEQ ID NO:1348, SEQ ID NO: 1354, SEQ ID NO: 1360, SEQ ID NO: 1366, SEQ ID NO:1372, SEQ ID NO: 1378, SEQ ID NO: 1384, SEQ ID NO: 1390, SEQ ID NO:1396, SEQ ID NO: 1402, SEQ ID NO: 1408, SEQ ID NO: 1414, SEQ ID NO:1420, SEQ ID NO: 1426, SEQ ID NO: 1432, SEQ ID NO: 1438, SEQ ID NO:1444, SEQ ID NO:
 1450. SEQ ID NO: 1456, SEQ ID NO: 1462, SEQ ID NO:1468, SEQ ID NO: 1474, SEQ ID NO: 1480, SEQ ID NO: 1486, SEQ ID NO:1492, SEQ ID NO: 1498, SEQ ID NO: 1504, SEQ ID NO: 1510, SEQ ID NO:1516, SEQ ID NO: 1522, SEQ ID NO: 1596, SEQ ID NO: 1528, SEQ ID NO:1534, SEQ ID NO: 1540, SEQ ID NO: 1546, SEQ ID NO: 1552, SEQ ID NO:1558, SEQ ID NO: 1564, SEQ ID NO: 1570, SEQ ID NO: 1576, SEQ ID NO: 1582and SEQ ID NO:
 1588. 6. The isolated antigen binding molecule of claim1, wherein the light chain variable region CDR2 comprises the amino acidsequence any one of SEQ ID NO: 401, SEQ ID NO: 407, SEQ ID NO: 413, SEQID NO: 419, SEQ ID NO: 425, SEQ ID NO: 431, SEQ ID NO: 437, SEQ ID NO:443, SEQ ID NO: 449, SEQ ID NO: 455, SEQ ID NO: 461, SEQ ID NO: 467, SEQID NO: 473, SEQ ID NO: 479, SEQ ID NO: 485, SEQ ID NO: 491, SEQ ID NO:497, SEQ ID NO: 503, SEQ ID NO: 509, SEQ ID NO: 515, SEQ ID NO: 521, SEQID NO: 527, SEQ ID NO: 533, SEQ ID NO: 539, SEQ ID NO: 545, SEQ ID NO:551, SEQ ID NO: 557, SEQ ID NO: 563, SEQ ID NO: 569, SEQ ID NO: 575, SEQID NO: 581, SEQ ID NO: 587, SEQ ID NO: 593, SEQ ID NO: 599, SEQ ID NO:605, SEQ ID NO: 611, SEQ ID NO: 617, SEQ ID NO: 623, SEQ ID NO: 629, SEQID NO: 635, SEQ ID NO: 641, SEQ ID NO: 647, SEQ ID NO: 653, SEQ ID NO:659, SEQ ID NO: 665, SEQ ID NO: 671, SEQ ID NO: 677, SEQ ID NO: 683, SEQID NO: 689, SEQ ID NO: 695, SEQ ID NO: 701, SEQ ID NO: 707, SEQ ID NO:713, SEQ ID NO: 719, SEQ ID NO: 725, SEQ ID NO: 731, SEQ ID NO: 737, SEQID NO: 743, SEQ ID NO: 749, SEQ ID NO: 755, SEQ ID NO: 761, SEQ ID NO:767, SEQ ID NO: 773, SEQ ID NO: 779, SEQ ID NO: 785, SEQ ID NO: 791, SEQID NO: 797, SEQ ID NO: 803, SEQ ID NO: 809, SEQ ID NO: 815, SEQ ID NO:821, SEQ ID NO: 827, SEQ ID NO: 833, SEQ ID NO: 839, SEQ ID NO: 845, SEQID NO: 851, SEQ ID NO: 857, SEQ ID NO: 863, SEQ ID NO: 869, SEQ ID NO:875, SEQ ID NO: 881, SEQ ID NO: 887, SEQ ID NO: 893, SEQ ID NO: 899, SEQID NO: 905, SEQ ID NO: 911, SEQ ID NO: 917, SEQ ID NO: 923, SEQ ID NO:929, SEQ ID NO: 935, SEQ ID NO: 941, SEQ ID NO: 947, SEQ ID NO: 953, SEQID NO: 959, SEQ ID NO: 965, SEQ ID NO: 971, SEQ ID NO: 977, SEQ ID NO:983, SEQ ID NO: 989, SEQ ID NO: 995, SEQ ID NO: 1001, SEQ ID NO: 1007,SEQ ID NO: 1013, SEQ ID NO: 1019, SEQ ID NO: 1025, SEQ ID NO: 1031, SEQID NO: 1037, SEQ ID NO: 1043, SEQ ID NO: 1049, SEQ ID NO: 1055, SEQ IDNO: 1061, SEQ ID NO: 1067, SEQ ID NO: 1073, SEQ ID NO: 1079, SEQ ID NO:1085, SEQ ID NO: 1091, SEQ ID NO: 1097, SEQ ID NO: 1103, SEQ ID NO:1109, SEQ ID NO: 1115, SEQ ID NO: 1121, SEQ ID NO: 1127, SEQ ID NO:1133, SEQ ID NO: 1139, SEQ ID NO: 1145, SEQ ID NO: 1151, SEQ ID NO:1157, SEQ ID NO: 1163, SEQ ID NO: 1169, SEQ ID NO: 1175, SEQ ID NO:1181, SEQ ID NO: 1187, SEQ ID NO: 1193, SEQ ID NO: 1199, SEQ ID NO:1205, SEQ ID NO: 1211, SEQ ID NO: 1217, SEQ ID NO: 1223, SEQ ID NO:1229, SEQ ID NO: 1235, SEQ ID NO: 1241, SEQ ID NO: 1247, SEQ ID NO:1253, SEQ ID NO: 1259, SEQ ID NO: 1265, SEQ ID NO: 1271, SEQ ID NO:1277, SEQ ID NO: 1283, SEQ ID NO: 1289, SEQ ID NO: 1295, SEQ ID NO:1301, SEQ ID NO: 1307, SEQ ID NO: 1313, SEQ ID NO: 1319, SEQ ID NO:1325, SEQ ID NO: 1331, SEQ ID NO: 1337, SEQ ID NO: 1343, SEQ ID NO:1349, SEQ ID NO: 1355, SEQ ID NO: 1361, SEQ ID NO: 1367, SEQ ID NO:1373, SEQ ID NO: 1379, SEQ ID NO: 1385, SEQ ID NO: 1391, SEQ ID NO:1397, SEQ ID NO: 1403, SEQ ID NO: 1409, SEQ ID NO: 1415, SEQ ID NO:1421, SEQ ID NO: 1427, SEQ ID NO: 1433, SEQ ID NO: 1439, SEQ ID NO:1445, SEQ ID NO: 1451, SEQ ID NO: 1457, SEQ ID NO: 1463, SEQ ID NO:1469, SEQ ID NO: 1475, SEQ ID NO: 1481, SEQ ID NO: 1487, SEQ ID NO:1493, SEQ ID NO: 1499, SEQ ID NO: 1505, SEQ ID NO: 1511, SEQ ID NO:1517, SEQ ID NO: 1523, SEQ ID NO: 1597, SEQ ID NO: 1529, SEQ ID NO:1535, SEQ ID NO: 1541, SEQ ID NO: 1547, SEQ ID NO: 1553, SEQ ID NO:1559, SEQ ID NO: 1565, SEQ ID NO: 1571, SEQ ID NO: 1577, SEQ ID NO: 1583and SEQ ID NO:
 1589. 7. The isolated antigen binding molecule of claim1, wherein the light chain variable region CDR3 comprises the amino acidsequence any one of SEQ ID NO: 402, SEQ ID NO: 408, SEQ ID NO: 414, SEQID NO: 420, SEQ ID NO: 426, SEQ ID NO: 432, SEQ ID NO: 438, SEQ ID NO:444, SEQ ID NO: 450, SEQ ID NO: 456, SEQ ID NO: 462, SEQ ID NO: 468, SEQID NO: 474, SEQ ID NO: 480, SEQ ID NO: 486, SEQ ID NO: 492, SEQ ID NO:498, SEQ ID NO: 504, SEQ ID NO: 510, SEQ ID NO: 516, SEQ ID NO: 522, SEQID NO: 528, SEQ ID NO: 534, SEQ ID NO: 540, SEQ ID NO: 546, SEQ ID NO:552, SEQ ID NO: 558, SEQ ID NO: 564, SEQ ID NO: 570, SEQ ID NO: 576, SEQID NO: 582, SEQ ID NO: 588, SEQ ID NO: 594, SEQ ID NO: 600, SEQ ID NO:606, SEQ ID NO: 612, SEQ ID NO: 618, SEQ ID NO: 624, SEQ ID NO: 630, SEQID NO: 636, SEQ ID NO: 642, SEQ ID NO: 648, SEQ ID NO: 654, SEQ ID NO:660, SEQ ID NO: 666, SEQ ID NO: 672, SEQ ID NO: 678, SEQ ID NO: 684, SEQID NO: 690, SEQ ID NO: 696, SEQ ID NO: 702, SEQ ID NO: 708, SEQ ID NO:714, SEQ ID NO: 720, SEQ ID NO: 726, SEQ ID NO: 732, SEQ ID NO: 738, SEQID NO: 744, SEQ ID NO: 750, SEQ ID NO: 756, SEQ ID NO: 762, SEQ ID NO:768, SEQ ID NO: 774, SEQ ID NO: 780, SEQ ID NO: 786, SEQ ID NO: 792, SEQID NO: 798, SEQ ID NO: 804, SEQ ID NO: 810, SEQ ID NO: 816, SEQ ID NO:822, SEQ ID NO: 828, SEQ ID NO: 834, SEQ ID NO: 840, SEQ ID NO: 846, SEQID NO: 852, SEQ ID NO: 858, SEQ ID NO: 864, SEQ ID NO: 870, SEQ ID NO:876, SEQ ID NO: 882, SEQ ID NO: 888, SEQ ID NO: 894, SEQ ID NO: 900, SEQID NO: 906, SEQ ID NO: 912, SEQ ID NO: 918, SEQ ID NO: 924, SEQ ID NO:930, SEQ ID NO: 936, SEQ ID NO: 942, SEQ ID NO: 948, SEQ ID NO: 954, SEQID NO: 960, SEQ ID NO: 966, SEQ ID NO: 972, SEQ ID NO: 978, SEQ ID NO:984, SEQ ID NO: 990, SEQ ID NO: 996, SEQ ID NO: 1002, SEQ ID NO: 1008,SEQ ID NO: 1014, SEQ ID NO: 1020, SEQ ID NO: 1026, SEQ ID NO: 1032, SEQID NO: 1038, SEQ ID NO: 1044, SEQ ID NO: 1050, SEQ ID NO: 1056, SEQ IDNO: 1062, SEQ ID NO: 1068, SEQ ID NO: 1074, SEQ ID NO: 1080, SEQ ID NO:1086, SEQ ID NO: 1092, SEQ ID NO: 1098, SEQ ID NO: 1104, SEQ ID NO:1110, SEQ ID NO: 1116, SEQ ID NO: 1122, SEQ ID NO: 1128, SEQ ID NO:1134, SEQ ID NO: 1140, SEQ ID NO: 1146, SEQ ID NO: 1152, SEQ ID NO:1158, SEQ ID NO: 1164, SEQ ID NO: 1170, SEQ ID NO: 1176, SEQ ID NO:1182, SEQ ID NO: 1188, SEQ ID NO: 1194, SEQ ID NO: 1200, SEQ ID NO:1206, SEQ ID NO: 1212, SEQ ID NO: 1218, SEQ ID NO: 1224, SEQ ID NO:1230, SEQ ID NO: 1236, SEQ ID NO: 1242, SEQ ID NO: 1248, SEQ ID NO:1254, SEQ ID NO: 1260, SEQ ID NO: 1266, SEQ ID NO: 1272, SEQ ID NO:1278, SEQ ID NO: 1284, SEQ ID NO: 1290, SEQ ID NO: 1296, SEQ ID NO:1302, SEQ ID NO: 1308, SEQ ID NO: 1314, SEQ ID NO: 1320, SEQ ID NO:1326, SEQ ID NO: 1332, SEQ ID NO: 1338, SEQ ID NO: 1344, SEQ ID NO:1350, SEQ ID NO: 1356, SEQ ID NO: 1362, SEQ ID NO: 1368, SEQ ID NO:1374, SEQ ID NO: 1380, SEQ ID NO: 1386, SEQ ID NO: 1392, SEQ ID NO:1398, SEQ ID NO: 1404, SEQ ID NO: 1410, SEQ ID NO: 1416, SEQ ID NO:1422, SEQ ID NO: 1428, SEQ ID NO: 1434, SEQ ID NO: 1440, SEQ ID NO:1446, SEQ ID NO: 1452, SEQ ID NO: 1458, SEQ ID NO: 1464, SEQ ID NO:1470, SEQ ID NO: 1476, SEQ ID NO: 1482, SEQ ID NO: 1488, SEQ ID NO:1494, SEQ ID NO: 1500, SEQ ID NO: 1506, SEQ ID NO: 1512, SEQ ID NO:1518, SEQ ID NO: 1524, SEQ ID NO: 1598, SEQ ID NO: 1530, SEQ ID NO:1536, SEQ ID NO: 1542, SEQ ID NO: 1548, SEQ ID NO: 1554, SEQ ID NO:1560, SEQ ID NO: 1566, SEQ ID NO: 1572, SEQ ID NO: 1578, SEQ ID NO: 1584and SEQ ID NO:
 1590. 8. The isolated antigen binding molecule of claim1, comprising a heavy chain comprising the heavy chain amino acidvariable sequence of any one of SEQ ID NO: 1 to SEQ ID NO: 97, SEQ IDNO: 195 to SEQ ID NO: 209, or SEQ ID NO: 225 to SEQ ID NO:
 310. 9. Theisolated antigen binding molecule of claim 1, comprising a light chaincomprising the light chain amino acid variable sequence of any one ofSEQ ID NO: 98 to SEQ ID NO: 194, SEQ ID NO: 210 to SEQ ID NO: 224, orSEQ ID NO: 311 to SEQ ID NO:
 396. 10. The isolated antigen bindingmolecule of claim 1, comprising: a heavy chain comprising the heavychain amino acid variable sequence of any one of SEQ ID NO: 1 to SEQ IDNO: 97, SEQ ID NO: 195 to SEQ ID NO: 209, or SEQ ID NO: 225 to SEQ IDNO: 310; and a light chain comprising the light chain amino acidvariable sequence of any one of SEQ ID NO: 98 to SEQ ID NO: 194, SEQ IDNO: 210 to SEQ ID NO: 224, or SEQ ID NO: 311 to SEQ ID NO:
 396. 11. Theisolated antigen binding molecule of claim 1, comprising: (a) a heavychain variable region comprising the amino acid sequence of SEQ ID NO:23; and a light chain variable region comprising the amino acid sequenceof SEQ ID NO: 120; (b) a heavy chain variable region comprising theamino acid sequence of SEQ ID NO: 29; and a light chain variable regioncomprising the amino acid sequence of SEQ ID NO: 126; (c) a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO: 45; anda light chain variable region comprising the amino acid sequence of SEQID NO: 142; (d) a heavy chain variable region comprising the amino acidsequence of SEQ ID NO: 46; and a light chain variable region comprisingthe amino acid sequence of SEQ ID NO: 143; (e) a heavy chain variableregion comprising the amino acid sequence of SEQ ID NO: 58; and a lightchain variable region comprising the amino acid sequence of SEQ ID NO:155; (f) a heavy chain variable region comprising the amino acidsequence of SEQ ID NO: 63; and a light chain variable region comprisingthe amino acid sequence of SEQ ID NO: 160; (g) a heavy chain variableregion comprising the amino acid sequence of SEQ ID NO: 67; and a lightchain variable region comprising the amino acid sequence of SEQ ID NO:164; (h) a heavy chain variable region comprising the amino acidsequence of SEQ ID NO: 72; and a light chain variable region comprisingthe amino acid sequence of SEQ ID NO: 169; or (i) a heavy chain variableregion comprising the amino acid sequence of SEQ ID NO: 80; and a lightchain variable region comprising the amino acid sequence of SEQ ID NO:177.
 12. The isolated antigen binding molecule of claim 1, wherein theantigen binding molecule is an antibody.
 13. The isolated antigenbinding molecule of claim 12, wherein the antibody is an intact humanantibody.
 14. The isolated antigen binding molecule of claim 12, whereinthe antibody is an antigen-binding fragment of an antibody.
 15. Theisolated antigen binding molecule of claim 12, wherein the antibody is achimeric antibody.
 16. The isolated antigen binding molecule of claim12, wherein the antibody is a humanized antibody.
 17. A compositioncomprising the isolated antigen binding molecule of claim 1 in an amountthat is pharmaceutically acceptable; and a pharmaceutically acceptablecarrier.